Novel Pyrimidinyl-DiazoSpiro Compounds

ABSTRACT

The invention relates to spiro derivatives, to the use of said derivatives intreating diseases and conditions mediated by modulation of voltage-gated sodium channels, to compositions containing said derivatives and processes for their preparation.

FIELD OF THE INVENTION

The invention relates to spiro derivatives, to the use of saidderivatives in treating diseases and conditions mediated by modulationof voltage-gated sodium channels, to compositions containing saidderivatives and processes for their preparation.

BACKGROUND OF THE INVENTION

Voltage-gated sodium channels are responsible for the initial phase ofthe action potential, which is a wave of electrical depolarisationusually initiated at the soma of the neuron and propagated along theaxon to the terminals. At the terminals, the action potential triggersthe influx of calcium and the release of neurotransmitter. Drugs, suchas lidocaine, that block voltage-gated sodium channels are used as localanaesthetics. Other sodium channel blockers, such as lamotrigine andcarbamazepine are used to treat epilepsy. In the latter case, partialinhibition of voltage-gated sodium channels reduces neuronalexcitability and reduces seizure propagation. In the case of localanaesthetics, regional block of sodium channels on sensory neuronsprevents the conduction of painful stimuli. A key feature of these drugsis their state-dependent mechanism of action. The drugs are thought tostabilise an inactivated conformation of the channel that is adoptedrapidly after the channel opens. This inactivated state provides arefractory period before the channel returns to its resting (closed)state ready to be reactivated. As a result, state-dependent sodiumchannel blockers inhibit the firing of neurons at high frequency, forexample in response to painful stimuli, and will help to preventrepetitive firing during periods of prolonged neuronal depolarisationthat might occur, for example, during a seizure. Action potentialstriggered at lower frequencies, for example in the heart, will not besignificantly affected by these drugs, although the safety margindiffers in each case, since at high enough concentrations each of thesedrugs is capable of blocking the resting or open states of the channels.

The voltage-gated sodium channel family is made up of 9 subtypes, fourof which are found in the brain, NaV1.1, 1.2, 1.3 and 1.6. Of the othersubtypes, NaV1.4 is found only in skeletal muscle, NaV1.5 is specific tocardiac muscle, and NaV1.7, 1.8, and 1.9 are found predominantly insensory neurons. The hypothesised binding site for state-dependentsodium channel blockers is the local anaesthetic (LA) binding site inthe inner vestibule of the pore on transmembrane S6 of domain IV.Critical residues are located in a highly conserved region among thedifferent subtypes, thus presenting a challenge for the design of newsubtype selective drugs. Drugs such as lidocaine, lamotrigine andcarbamazepine do not distinguish between the subtypes. However,selectivity can be achieved, and can be further enhanced functionally,as a result of the different frequencies at which the channels operate.

Drugs that block voltage-gated sodium channels in a state-dependentmanner are also used in the treatment of bipolar disorder, either toreduce symptoms of mania or depression, or as mood stabilisers toprevent the emergence of mood episodes. Clinical and preclinicalevidence also suggests that state-dependent sodium channel blockers mayhelp to reduce the symptoms of schizophrenia. For example, lamotriginehas been shown to reduce symptoms of psychosis induced by ketamine inhealthy human volunteers, and furthermore, studies in patients suggestthat the drug can augment the antipsychotic efficacy of some atypicalantipsychotic drugs, such as clozapine or olanzapine. It is hypothesisedthat efficacy in these psychiatric disorders may result in part from areduction of excessive glutamate release. The reduction in glutamaterelease is thought to be a consequence of sodium channel inhibition inkey brain areas, such as the frontal cortex. However, interaction withvoltage-gated calcium channels may also contribute to the efficacy ofthese drugs.

WO 2007/042240 (Glaxo Group Limited) describes a series of quaternaryalpha-aminocarboxamide derivatives as modulators of voltage-gated sodiumchannels.

The object of the invention is to identify alternative compounds whichmodulate voltage-gated sodium channels.

SUMMARY OF THE INVENTION

According to a first aspect, the invention provides a compound offormula (I) which is7-methyl-2-[4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]nonan-6-one:

or a pharmaceutically acceptable salt or solvate thereof.

DETAILED DESCRIPTION OF THE INVENTION

A reference to a compound of the formula (I) and sub-groups thereof alsoincludes ionic forms, salts, solvates, isomers (including geometric andstereochemical isomers), tautomers, N-oxides, esters, prodrugs, isotopesand protected forms thereof, for example, as discussed below;preferably, the salts or tautomers or isomers or N-oxides or solvatesthereof; and more preferably, the salts or tautomers or N-oxides orsolvates thereof, even more preferably the salts or tautomers orsolvates thereof. Hereinafter, compounds and their ionic forms, salts,solvates, isomers (including geometric and stereochemical isomers),tautomers, N-oxides, esters, prodrugs, isotopes and protected formsthereof as defined in any aspect of the invention (except intermediatecompounds in chemical processes) are referred to as “compounds of theinvention”.

Compounds of formula (I) can exist in the form of salts, for exampleacid addition salts or, in certain cases salts of organic and inorganicbases such as carboxylate, sulfonate and phosphate salts. All such saltsare within the scope of this invention, and references to compounds offormula (I) include the salt forms of the compounds.

The salts of the present invention can be synthesized from the parentcompound that contains a basic or acidic moiety by conventional chemicalmethods such as methods described in Pharmaceutical Salts: Properties,Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth(Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002.Generally, such salts can be prepared by reacting the free acid or baseforms of these compounds with the appropriate base or acid in water orin an organic solvent, or in a mixture of the two; generally, nonaqueousmedia such as dichloromethane, 1,4-dioxane, ether, ethyl acetate,ethanol, isopropanol, or acetonitrile are used.

Acid addition salts (mono- or di-salts) may be formed with a widevariety of acids, both inorganic and organic. Examples of acid additionsalts include mono- or di-salts formed with an acid selected from thegroup consisting of acetic, 2,2-dichloroacetic, adipic, alginic,ascorbic (e.g. L-ascorbic), L-aspartic, benzenesulfonic, benzoic,4-acetamidobenzoic, butanoic, (+) camphoric, camphor-sulfonic,(+)-(1S)-camphor-10-sulfonic, capric, caproic, caprylic, cinnamic,citric, cyclamic, dodecylsulfuric, ethane-1,2-disulfonic,ethanesulfonic, 2-hydroxyethanesulfonic, formic, fumaric, galactaric,gentisic, glucoheptonic, D-gluconic, glucuronic (e.g. D-glucuronic),glutamic (e.g. L-glutamic), α-oxoglutaric, glycolic, hippuric,hydrohalic acids (e.g. hydrobromic, hydrochloric, hydriodic),isethionic, lactic (e.g. (+)-L-lactic, (±)-DL-lactic), lactobionic,maleic, malic, (−)-L-malic, malonic, (±)-DL-mandelic, methanesulfonic,naphthalene-2-sulfonic, naphthalene-1,5-disulfonic,1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic,palmitic, pamoic, phosphoric, propionic, pyruvic, L-pyroglutamic,salicylic, 4-amino-salicylic, sebacic, stearic, succinic, sulfuric,tannic, (+)-L-tartaric, thiocyanic, p-toluenesulfonic, undecylenic andvaleric acids, as well as acylated amino acids and cation exchangeresins.

One particular group of salts consists of salts formed from acetic,hydrochloric, hydriodic, phosphoric, nitric, sulfuric, citric, lactic,succinic, maleic, malic, isethionic, fumaric, benzenesulfonic,toluenesulfonic, sulfuric, methanesulfonic (mesylate), ethanesulfonic,naphthalenesulfonic, valeric, acetic, propanoic, butanoic, malonic,glucuronic and lactobionic acids. One particular salt is thehydrochloride salt. Another particular salt is the hydrogensulfate.

Where the compounds of the formula (I) contain an amine function, thesemay form quaternary ammonium salts, for example by reaction with analkylating agent according to methods well known to the skilled person.Such quaternary ammonium compounds are within the scope of formula (I).

The compounds of the invention may exist as mono- or di-salts dependingupon the pKa of the acid from which the salt is formed.

The salt forms of the compounds of the invention are typicallypharmaceutically acceptable salts, and examples of pharmaceuticallyacceptable salts are discussed in Berge et al., 1977, “PharmaceuticallyAcceptable Salts,” J. Pharm. Sci., Vol. 66, pp. 1-19. However, saltsthat are not pharmaceutically acceptable may also be prepared asintermediate forms which may then be converted into pharmaceuticallyacceptable salts. Such non-pharmaceutically acceptable salts forms,which may be useful, for example, in the purification or separation ofthe compounds of the invention, also form part of the invention.

In one embodiment, the compound of formula (I) is(2R,55)-7-Methyl-2-[4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]nonan-6-onehydrochloride (E1)

In an alternative embodiment, the compound of formula (I) is(2R,5S)-7-Methyl-2-[4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]nonan-6-onesulfuric acid salt (E2).

Those skilled in the art of organic chemistry will appreciate that manyorganic compounds can form complexes with solvents in which they arereacted or from which they are precipitated or crystallized. Thesecomplexes are known as “solvates”. For example, a complex with water isknown as a “hydrate”. Pharmaceutically acceptable solvates of thecompound of the invention are within the scope of the invention. In oneembodiment, the pharmaceutically acceptable solvates of the compounds ofthe invention include the hydrate thereof. In a further embodiment, thecompound of formula (I) is(2R,5S)-7-Methyl-2-[4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]nonan-6-onesulfuric acid salt hydrate (E3).

Compounds of the formula (I) containing an amine function may also formN-oxides. A reference herein to a compound of the formula (I) thatcontains an amine function also includes the N-oxide.

Where a compound contains several amine functions, one or more than onenitrogen atom may be oxidised to form an N-oxide. Particular examples ofN-oxides are the N-oxides of a tertiary amine or a nitrogen atom of anitrogen-containing heterocycle.

N-Oxides can be formed by treatment of the corresponding amine with anoxidizing agent such as hydrogen peroxide or a per-acid (e.g. aperoxycarboxylic acid), see for example Advanced Organic Chemistry, byJerry March, 4th Edition, Wiley Interscience, pages. More particularly,N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977,7, 509-514) in which the amine compound is reacted withm-chloroperoxybenzoic acid (MCPBA), for example, in an inert solventsuch as dichloromethane.

It will be appreciated by those skilled in the art that certainprotected derivatives of compounds of formula (I), which may be madeprior to a final deprotection stage, may not possess pharmacologicalactivity as such, but may, in certain instances, be administered orallyor parenterally and thereafter metabolised in the body to form compoundsof the invention which are pharmacologically active. Such derivativesmay therefore be described as “prodrugs”. All such prodrugs of compoundsof the invention are included within the scope of the invention.Examples of pro-drug functionality suitable for the compounds of thepresent invention are described in Drugs of Today, Volume 19, Number 9,1983, pp 499-538 and in Topics in Chemistry, Chapter 31, pp 306-316 andin “Design of Prodrugs” by H. Bundgaard, Elsevier, 1985, Chapter 1 (thedisclosures in which documents are incorporated herein by reference). Itwill further be appreciated by those skilled in the art, that certainmoieties, known to those skilled in the art as “pro-moieties”, forexample as described by H. Bundgaard in “Design of Prodrugs” (thedisclosure in which document is incorporated herein by reference) may beplaced on appropriate functionalities when such functionalities arepresent within compounds of the invention.

Also included within the scope of the compound and various salts of theinvention are polymorphs thereof.

Compounds of the formula (I) may exist in a number of differentgeometric isomeric, and tautomeric forms and references to compounds ofthe formula (I) include all such forms. For the avoidance of doubt,where a compound can exist in one of several geometric isomeric ortautomeric forms and only one is specifically described or shown, allothers are nevertheless embraced by formula (I).

In one embodiment, the invention provides compounds of any one offormulae (Ia)-(Id):

In a further embodiment, the invention provides compounds of formula(Ia). Representative examples of compounds of formula (Ia) includeExamples 1-3 described herein.

The present invention includes all pharmaceutically acceptableisotopically-labeled compounds of the invention, i.e. compounds offormula (I), wherein one or more atoms are replaced by atoms having thesame atomic number, but an atomic mass or mass number different from theatomic mass or mass number usually found in nature.

Examples of isotopes suitable for inclusion in the compounds of theinvention comprise isotopes of hydrogen, such as ²H (D) and ³H (T),carbon, such as ¹³C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl, fluorine, suchas ¹⁸F, iodine, such as ¹²³I, ¹²⁵I and ¹³¹I, nitrogen, such as ¹³N and¹⁵N, oxygen, such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, andsulfur, such as ³⁵S.

Certain isotopically-labelled compounds of formula (I), for example,those incorporating a radioactive isotope, are useful in drug and/orsubstrate tissue distribution studies. The compounds of formula (I) canalso have valuable diagnostic properties in that they can be used fordetecting or identifying the formation of a complex between a labelledcompound and other molecules, peptides, proteins, enzymes or receptors.The detecting or identifying methods can use compounds that are labelledwith labelling agents such as radioisotopes, enzymes, fluorescentsubstances, luminous substances (for example, luminol, luminolderivatives, luciferin, aequorin and luciferase), etc. The radioactiveisotopes tritium, i.e. ³H (T), and carbon-14, i.e. ¹⁴C, are particularlyuseful for this purpose in view of their ease of incorporation and readymeans of detection.

Substitution with heavier isotopes such as deuterium, i.e. ²H (D), mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining target occupancy.

Isotopically-labeled compounds of formula (I) can generally be preparedby conventional techniques known to those skilled in the art or byprocesses analogous to those described in the accompanying Examples andPreparations using an appropriate isotopically-labeled reagents in placeof the non-labeled reagent previously employed.

According to a further aspect of the invention there is provided aprocess for preparing a compound of formula (I) as herein defined whichcomprises:

(a) forming a compound of formula (I) by performing a ring closurereaction of a compound of formula (II) followed by reduction of theresulting imine (IIA):

(b) deprotection of a protected derivative of a compound of formula (I);

(c) optional formation of a pharmaceutically acceptable salt of acompound of formula (I).

Process (a) typically comprises treating the compound of formula (II)with a suitable reagent, such as silver trifluoromethanesulfonate(AgOTf), with stirring at a suitable temperature, such as 40° C., for asuitable time period, such as 3 to 7 days, followed by reduction of theresulting imine (IIA) by a hydride reducing agent such as sodiumtriacetoxyborohydride in a solvent system such as aqueous hydrochlorideacid and dichloromethane, or by using borane or a modified borane suchas tertiarybutylamine:borane complex, or hydrogenation over a suitablecatalyst such as platinum.

Compounds of formula (II) may be prepared in accordance with Scheme 1:

wherein L¹ represents a suitable leaving group, such as a halogen atom(i.e. bromine) and L² represents a suitable leaving group, such as ahalogen atom (i.e. iodine) and P¹ represents a suitable protectinggroup, such as Boc.

Step (i) typically comprises reacting a compound of formula (III) with acompound of formula (IV) in the presence of a suitable solvent, such asdichloroethane (DCE).

Step (ii) typically comprises reacting a compound of formula (V) with acompound of formula (VI) in the presence of a suitable base such aspotassium tert-butoxide and a suitable solvent, such as tetrahydrofuran(THF).

Step (iii) typically comprises deprotecting a compound of formula (VII)with a suitable acidic reagent, such as citric acid.

Step (iv) comprises a chiral resolution in which one chiraldiastereomeric salt form of (VIII) is crystallised and separated from amore soluble epimer, for example by fractional crystallisation of (VIII)with a chiral acid such as mandelic acid or2-(6-methoxy-2-naphthyl)propanoic acid in a suitable solvent such asTHF, acetonitrile or isopropyl alcohol. The chiral form (VIII)^(a) maybe liberated by treating the salt with a base, such as a resin-boundbase, in a suitable solvent such as methanol.

Step (v) typically comprises treating a compound of formula (VIII) witha suitable amine protecting reagent, such as Boc₂O, in the presence of asuitable solvent, such as dichloromethane (DCM).

Step (vi) typically comprises reacting a terminal alkyne of formula (IX)or (VIII) with a compound of formula (X) in the presence of a suitablereagent, such as copper iodide, a suitable catalyst, such asPdCl₂(Ph₃P)₂, a suitable base, such as diethylamine (Et₂NH) ordiisopropylamine and a suitable solvent, such as tetrahydrofuran, ortertiarybutyl methyl ether.

Step (vii) typically comprises deprotecting a compound of formula (XI)with a suitable acidic reagent, such as trifluoroacetic acid (TFA) inthe presence of a suitable solvent, such as dichloromethane (DCM) oralternatively by using sulphuric acid in a solvent such as 1,4-dioxane.

Compounds of formula (X) may be prepared in accordance with Scheme 2:

wherein L² represents a suitable leaving group, such as a halogen atom(i.e. iodine), L³ represents a suitable leaving group, such as a halogenatom (i.e. chlorine) and L⁴ represents a suitable leaving group, such asa halogen atom (i.e. chlorine).

Step (i) typically comprises reacting a compound of formula (XX) with acompound of formula ( )KI) in the presence of a suitable reagent, suchas sodium carbonate, a suitable catalyst, such as PdCl₂(Ph₃P)₂, and asuitable solvent, such as dimethoxyethane/water.

When L³ represents chlorine and L² represents iodine, step (ii)typically comprises reacting a compound of formula (MI) with hydrogeniodide.

Compounds of formula (IIA) may be prepared in accordance with Scheme 3:

Step (i) typically comprises condensation of a compound of formula (III)with a carboxyaldehyde compound, including for example a compound offormula (XXVII) (the preparation of which is described below in Scheme4), in the presence of a dehydrating agent such as magnesium sulfate ormolecular sieves in a solvent such as dichloromethane.

Step (ii) typically comprises a [3+2] cycloaddition reaction with phenylvinyl sulfone catalysed by a transition metal salt such as a silver orcopper salt, in the presence of a base and optionally a chiral phosphineligand.

Step (iii) typically comprises elimination of the phenyl vinyl sulfonetypically with a strong base such as potassium tert-butoxide.

The carboxaldehyde compound of formula (XXVII) suitable for reactingwith a compound of formula (III) in Scheme 3, may be commerciallyavailable but may also be prepared according to Scheme 4:

Step (i) typically comprises an acid catalysed (for examplehydrochloride acid) alkoholysis of a 2-cyanopyrimdine with, for example,methanol.

Step (ii) comprises a reduction to an aldehyde using a hindered hydridereducing agent, for example diisobutyl aluminium hydride, in a suitablesolvent such as toluene or dichloromethane.

Compounds of formulae (III), (IV), (VI), (XX), (XXI) and (XXV) areeither known or may be prepared in accordance with known methodology.

It will be appreciated by those skilled in organic synthesis that two ormore chemical steps in the schemes above may be run sequentially withoutisolation of intermediate materials.

It may also be recognised that isomer separation may occur at anysuitable stage in the synthetic sequence. It should be stressed thatsuch chiral separation forms a key aspect of the invention and that suchseparation may be conducted in accordance with the methodology describedherein or may be conducted in accordance with known methodology.

It is also recognised that it may be beneficial to temporarily form aprotected derivative of an intermediate in the synthesis, for example, aBoc-protected amine, in order to facilitate chromatographic separation,chiral resolution or to give improved solubility or yields in particularsteps.

As discussed hereinabove, it is believed that compounds of the inventionmay be useful for the treatment of diseases and conditions mediated bymodulation of voltage-gated sodium channels.

In one embodiment, the compounds will be state-dependent sodium channelinhibitors.

In another embodiment, the compounds will be subtype NaV1.7 sodiumchannel state-dependent inhibitors.

In another embodiment, the compounds will be state-dependent sodiumchannel inhibitors which have a suitable developability profile on oraladministration, for example in terms of exposure (Cmax) and/orbioavailability.

In one embodiment, the compounds will be sodium channel inhibitors.

In another embodiment, the compounds will be subtype NaV1.7 sodiumchannel inhibitors.

In another embodiment, the compounds will be sodium channel inhibitorswhich have a suitable developability profile on oral administration, forexample in terms of exposure (Cmax) and/or bioavailability.

According to a further aspect of the invention, there is providedcompounds of the invention for use as a medicament, preferably a humanmedicament.

According to a further aspect the invention provides the use ofcompounds of the invention in the manufacture of a medicament fortreating or preventing a disease or condition mediated by modulation ofvoltage-gated sodium channels.

In one particular embodiment, compounds of the invention may be usefulas analgesics. For example they may be useful in the treatment ofchronic inflammatory pain (e.g. pain associated with rheumatoidarthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis andjuvenile arthritis); musculoskeletal pain; lower back and neck pain;sprains and strains; neuropathic pain; sympathetically maintained pain;myositis; pain associated with cancer and fibromyalgia; pain associatedwith migraine; pain associated with influenza or other viral infections,such as the common cold; rheumatic fever; pain associated withfunctional bowel disorders such as non-ulcer dyspepsia, non-cardiacchest pain and irritable bowel syndrome; pain associated with myocardialischemia; post operative pain; headache; toothache; and dysmenorrhea.

Compounds of the invention may be useful in the treatment of neuropathicpain.

Neuropathic pain syndromes can develop following neuronal injury and theresulting pain may persist for months or years, even after the originalinjury has healed. Neuronal injury may occur in the peripheral nerves,dorsal roots, spinal cord or certain regions in the brain. Neuropathicpain syndromes are traditionally classified according to the disease orevent that precipitated them. Neuropathic pain syndromes include:diabetic neuropathy; sciatica; non-specific lower back pain; multiplesclerosis pain; fibromyalgia; HIV-related neuropathy; post-herpeticneuralgia; trigeminal neuralgia; and pain resulting from physicaltrauma, amputation, cancer, toxins or chronic inflammatory conditions.These conditions are difficult to treat and although several drugs areknown to have limited efficacy, complete pain control is rarelyachieved. The symptoms of neuropathic pain are incredibly heterogeneousand are often described as spontaneous shooting and lancinating pain, orongoing, burning pain. In addition, there is pain associated withnormally non-painful sensations such as “pins and needles”(paraesthesias and dysesthesias), increased sensitivity to touch(hyperesthesia), painful sensation following innocuous stimulation(dynamic, static or thermal allodynia), increased sensitivity to noxiousstimuli (thermal, cold, mechanical hyperalgesia), continuing painsensation after removal of the stimulation (hyperpathia) or an absenceof or deficit in selective sensory pathways (hypoalgesia).

Compounds of the invention may also be useful in the amelioration ofinflammatory disorders, for example in the treatment of skin conditions(e.g. sunburn, burns, eczema, dermatitis, psoriasis); ophthalmicdiseases; lung disorders (e.g. asthma, bronchitis, emphysema, allergicrhinitis, non-allergic rhinitis, cough, respiratory distress syndrome,pigeon fancier's disease, farmer's lung, chronic obstructive pulmonarydisease, (COPD); gastrointestinal tract disorders (e.g. Crohn's disease,ulcerative colitis, coeliac disease, regional ileitis, irritable bowelsyndrome, inflammatory bowel disease, gastroesophageal reflux disease);other conditions with an inflammatory component such as migraine,multiple sclerosis, myocardial ischemia.

In one embodiment, the compounds of the invention are useful in thetreatment of neuropathic pain or inflammatory pain as described herein.

Without wishing to be bound by theory, other diseases or conditions thatmay be mediated by modulation of voltage-gated sodium channels areselected from the list consisting of [the numbers in brackets after thelisted diseases below refer to the classification code in Diagnostic andStatistical Manual of Mental Disorders, 4th Edition, published by theAmerican Psychiatric Association (DSM-IV) and/or the InternationalClassification of Diseases, 10th Edition (ICD-10)]:

i) Depression and mood disorders including Major Depressive Episode,Manic Episode, Mixed Episode and Hypomanic Episode; Depressive Disordersincluding Major Depressive Disorder, Dysthymic Disorder (300.4),Depressive Disorder Not Otherwise Specified (311); Bipolar Disordersincluding Bipolar I Disorder, Bipolar II Disorder (Recurrent MajorDepressive Episodes with Hypomanic Episodes) (296.89), CyclothymicDisorder (301.13) and Bipolar Disorder Not Otherwise Specified (296.80);Other Mood Disorders including Mood Disorder Due to a General MedicalCondition (293.83) which includes the subtypes With Depressive Features,With Major Depressive-like Episode, With Manic Features and With MixedFeatures), Substance-Induced Mood Disorder (including the subtypes WithDepressive Features, With Manic Features and With Mixed Features) andMood Disorder Not Otherwise Specified (296.90):

ii) Schizophrenia including the subtypes Paranoid Type (295.30),Disorganised Type (295.10), Catatonic Type (295.20), UndifferentiatedType (295.90) and Residual Type (295.60); Schizophreniform Disorder(295.40); Schizoaffective Disorder (295.70) including the subtypesBipolar Type and Depressive Type; Delusional Disorder (297.1) includingthe subtypes Erotomanic Type, Grandiose Type, Jealous Type, PersecutoryType, Somatic Type, Mixed Type and Unspecified Type; Brief PsychoticDisorder (298.8); Shared Psychotic Disorder (297.3); Psychotic DisorderDue to a General Medical Condition including the subtypes With Delusionsand With Hallucinations; Substance-Induced Psychotic Disorder includingthe subtypes With Delusions (293.81) and With Hallucinations (293.82);and Psychotic Disorder Not Otherwise Specified (298.9).

iii) Anxiety disorders including Panic Attack; Panic Disorder includingPanic Disorder without Agoraphobia (300.01) and Panic Disorder withAgoraphobia (300.21); Agoraphobia; Agoraphobia Without History of PanicDisorder (300.22), Specific Phobia (300.29, formerly Simple Phobia)including the subtypes Animal Type, Natural Environment Type,Blood-Injection-Injury Type, Situational Type and Other Type), SocialPhobia (Social Anxiety Disorder, 300.23), Obsessive-Compulsive Disorder(300.3), Posttraumatic Stress Disorder (309.81), Acute Stress Disorder(308.3), Generalized Anxiety Disorder (300.02), Anxiety Disorder Due toa General Medical Condition (293.84), Substance-Induced AnxietyDisorder, Separation Anxiety Disorder (309.21), Adjustment Disorderswith Anxiety (309.24) and Anxiety Disorder Not Otherwise Specified(300.00):

iv) Substance-related disorders including Substance Use Disorders suchas Substance Dependence, Substance Craving and Substance Abuse;Substance-Induced Disorders such as Substance Intoxication, SubstanceWithdrawal, Substance-Induced Delirium, Substance-Induced PersistingDementia, Substance-Induced Persisting Amnestic Disorder,Substance-Induced Psychotic Disorder, Substance-Induced Mood Disorder,Substance-Induced Anxiety Disorder, Substance-Induced SexualDysfunction, Substance-Induced Sleep Disorder and HallucinogenPersisting Perception Disorder (Flashbacks); Alcohol-Related Disorderssuch as Alcohol Dependence (303.90), Alcohol Abuse (305.00), AlcoholIntoxication (303.00), Alcohol Withdrawal (291.81), Alcohol IntoxicationDelirium, Alcohol Withdrawal Delirium, Alcohol-Induced PersistingDementia, Alcohol-Induced Persisting Amnestic Disorder, Alcohol-InducedPsychotic Disorder, Alcohol-Induced Mood Disorder, Alcohol-InducedAnxiety Disorder, Alcohol-Induced Sexual Dysfunction, Alcohol-InducedSleep Disorder and Alcohol-Related Disorder Not Otherwise Specified(291.9); Amphetamine (or Amphetamine-Like)-Related Disorders such asAmphetamine Dependence (304.40), Amphetamine Abuse (305.70), AmphetamineIntoxication (292.89), Amphetamine Withdrawal (292.0), AmphetamineIntoxication Delirium, Amphetamine Induced Psychotic Disorder,Amphetamine-Induced Mood Disorder, Amphetamine-Induced Anxiety Disorder,Amphetamine-Induced Sexual Dysfunction, Amphetamine-Induced SleepDisorder and Amphetamine-Related Disorder Not Otherwise Specified(292.9); Caffeine Related Disorders such as Caffeine Intoxication(305.90), Caffeine-Induced Anxiety Disorder, Caffeine-Induced SleepDisorder and Caffeine-Related Disorder Not Otherwise Specified (292.9);Cannabis-Related Disorders such as Cannabis Dependence (304.30),Cannabis Abuse (305.20), Cannabis Intoxication (292.89), CannabisIntoxication Delirium, Cannabis-Induced Psychotic Disorder,Cannabis-Induced Anxiety Disorder and Cannabis-Related Disorder NotOtherwise Specified (292.9); Cocaine-Related Disorders such as CocaineDependence (304.20), Cocaine Abuse (305.60), Cocaine Intoxication(292.89), Cocaine Withdrawal (292.0), Cocaine Intoxication Delirium,Cocaine-Induced Psychotic Disorder, Cocaine-Induced Mood Disorder,Cocaine-Induced Anxiety Disorder, Cocaine-Induced Sexual Dysfunction,Cocaine-Induced Sleep Disorder and Cocaine-Related Disorder NotOtherwise Specified (292.9); Hallucinogen-Related Disorders such asHallucinogen Dependence (304.50), Hallucinogen Abuse (305.30),Hallucinogen Intoxication (292.89), Hallucinogen Persisting PerceptionDisorder (Flashbacks) (292.89), Hallucinogen Intoxication Delirium,Hallucinogen-Induced Psychotic Disorder, Hallucinogen-Induced MoodDisorder, Hallucinogen-Induced Anxiety Disorder and Hallucinogen-RelatedDisorder Not Otherwise Specified (292.9); Inhalant-Related Disorderssuch as Inhalant Dependence (304.60), Inhalant Abuse (305.90), InhalantIntoxication (292.89), Inhalant Intoxication Delirium, Inhalant-InducedPersisting Dementia, Inhalant-Induced Psychotic Disorder,Inhalant-Induced Mood Disorder, Inhalant-Induced Anxiety Disorder andInhalant-Related Disorder Not Otherwise Specified (292.9);Nicotine-Related Disorders such as Nicotine Dependence (305.1), NicotineWithdrawal (292.0) and Nicotine-Related Disorder Not Otherwise Specified(292.9); Opioid-Related Disorders such as Opioid Dependence (304.00),Opioid Abuse (305.50), Opioid Intoxication (292.89), Opioid Withdrawal(292.0), Opioid Intoxication Delirium, Opioid-Induced PsychoticDisorder, Opioid-Induced Mood Disorder, Opioid-Induced SexualDysfunction, Opioid-Induced Sleep Disorder and Opioid-Related DisorderNot Otherwise Specified (292.9); Phencyclidine (orPhencyclidine-Like)-Related Disorders such as Phencyclidine Dependence(304.60), Phencyclidine Abuse (305.90), Phencyclidine Intoxication(292.89), Phencyclidine Intoxication Delirium, Phencyclidine-InducedPsychotic Disorder, Phencyclidine-Induced Mood Disorder,Phencyclidine-Induced Anxiety Disorder and Phencyclidine-RelatedDisorder Not Otherwise Specified (292.9); Sedative-, Hypnotic-, orAnxiolytic-Related Disorders such as Sedative, Hypnotic, or AnxiolyticDependence (304.10), Sedative, Hypnotic, or Anxiolytic Abuse (305.40),Sedative, Hypnotic, or Anxiolytic Intoxication (292.89), Sedative,Hypnotic, or Anxiolytic Withdrawal (292.0), Sedative, Hypnotic, orAnxiolytic Intoxication Delirium, Sedative, Hypnotic, or AnxiolyticWithdrawal Delirium, Sedative-, Hypnotic-, or Anxiolytic-PersistingDementia, Sedative-, Hypnotic-, or Anxiolytic- Persisting AmnesticDisorder, Sedative-, Hypnotic-, or Anxiolytic-Induced PsychoticDisorder, Sedative-, Hypnotic-, or Anxiolytic-lnduced Mood Disorder,Sedative-, Hypnotic-, or Anxiolytic-lnduced Anxiety Disorder Sedative-,Hypnotic-, or Anxiolytic-lnduced Sexual Dysfunction, Sedative-,Hypnotic-, or Anxiolytic-Induced Sleep Disorder and Sedative-,Hypnotic-, or Anxiolytic-Related Disorder Not Otherwise Specified(292.9); Polysubstance-Related Disorder such as Polysubstance Dependence(304.80); and Other (or Unknown) Substance-Related Disorders such asAnabolic Steroids, Nitrate Inhalants and Nitrous Oxide:

v) Enhancement of cognition including the treatment of cognitionimpairment in other diseases such as schizophrenia, bipolar disorder,depression, other psychiatric disorders and psychotic conditionsassociated with cognitive impairment, e.g. Alzheimer's disease:

vi) Sleep disorders including primary sleep disorders such as Dyssomniassuch as Primary Insomnia (307.42), Primary Hypersomnia (307.44),Narcolepsy (347), Breathing-Related

Sleep Disorders (780.59), Circadian Rhythm Sleep Disorder (307.45) andDyssomnia Not Otherwise Specified (307.47); primary sleep disorders suchas Parasomnias such as Nightmare Disorder (307.47), Sleep TerrorDisorder (307.46), Sleepwalking Disorder (307.46) and Parasomnia NotOtherwise Specified (307.47); Sleep Disorders Related to Another MentalDisorder such as Insomnia Related to Another Mental Disorder (307.42)and Hypersomnia Related to Another Mental Disorder (307.44); SleepDisorder Due to a General Medical Condition, in particular sleepdisturbances associated with such diseases as neurological disorders,neuropathic pain, restless leg syndrome, heart and lung diseases; andSubstance-Induced Sleep Disorder including the subtypes Insomnia Type,Hypersomnia Type, Parasomnia Type and Mixed Type; sleep apnea andjet-lag syndrome:

vi) Eating disorders such as Anorexia Nervosa (307.1) including thesubtypes Restricting Type and Binge-Eating/Purging Type; Bulimia Nervosa(307.51) including the subtypes Purging Type and Nonpurging Type;Obesity; Compulsive Eating Disorder; Binge Eating Disorder; and EatingDisorder Not Otherwise Specified (307.50):

vii) Autism Spectrum Disorders including Autistic Disorder (299.00),Asperger's Disorder (299.80), Rett's Disorder (299.80), ChildhoodDisintegrative Disorder (299.10) and Pervasive Disorder Not OtherwiseSpecified (299.80, including Atypical Autism).

viii) Attention-Deficit/Hyperactivity Disorder including the subtypesAttention-Deficit/Hyperactivity Disorder Combined Type (314.01),Attention-Deficit/Hyperactivity Disorder Predominantly Inattentive Type(314.00), Attention-Deficit/Hyperactivity Disorder Hyperactive-ImpulseType (314.01) and Attention-Deficit/Hyperactivity Disorder Not OtherwiseSpecified (314.9); Hyperkinetic Disorder; Disruptive Behaviour Disorderssuch as Conduct Disorder including the subtypes childhood-onset type(321.81), Adolescent-Onset Type (312.82) and Unspecified Onset (312.89),Oppositional Defiant Disorder (313.81) and Disruptive Behaviour DisorderNot Otherwise Specified; and Tic Disorders such as Tourette's Disorder(307.23):

ix) Personality Disorders including the subtypes Paranoid PersonalityDisorder (301.0), Schizoid Personality Disorder (301.20), SchizotypalPersonality Disorder (301,22), Antisocial Personality Disorder (301.7),Borderline Personality Disorder (301,83), Histrionic PersonalityDisorder (301.50), Narcissistic Personality Disorder (301,81), AvoidantPersonality Disorder (301.82), Dependent Personality Disorder (301.6),Obsessive-Compulsive Personality Disorder (301.4) and PersonalityDisorder Not Otherwise Specified (301.9): and

x) Sexual dysfunctions including Sexual Desire Disorders such asHypoactive Sexual Desire Disorder (302.71), and Sexual Aversion Disorder(302.79); sexual arousal disorders such as Female Sexual ArousalDisorder (302.72) and Male Erectile Disorder (302.72); orgasmicdisorders such as Female Orgasmic Disorder (302.73), Male OrgasmicDisorder (302.74) and Premature Ejaculation (302.75); sexual paindisorder such as Dyspareunia (302.76) and Vaginismus (306.51); SexualDysfunction Not Otherwise Specified (302.70); paraphilias such asExhibitionism (302.4), Fetishism (302.81), Frotteurism (302.89),Pedophilia (302.2), Sexual Masochism (302.83), Sexual Sadism (302.84),Transvestic Fetishism (302.3), Voyeurism (302.82) and Paraphilia NotOtherwise Specified (302.9); gender identity disorders such as GenderIdentity Disorder in Children (302.6) and Gender Identity Disorder inAdolescents or Adults (302.85); and Sexual Disorder Not OtherwiseSpecified (302.9).

xi) Impulse control disorder” including: Intermittent Explosive Disorder(312.34), Kleptomania (312.32), Pathological Gambling (312.31),Pyromania (312.33), Trichotillomania (312.39), Impulse-Control DisordersNot Otherwise Specified (312.3), Binge Eating, Compulsive Buying,Compulsive Sexual Behaviour and Compulsive Hoarding.

In another embodiment, diseases or conditions that may be mediated bymodulation of voltage gated sodium channels are depression or mooddisorders

In another embodiment, diseases or conditions that may be mediated bymodulation of voltage gated sodium channels are substance relateddisorders.

In a further embodiment, diseases or conditions that may be mediated bymodulation of voltage gated sodium channels are Bipolar Disorders(including Bipolar I Disorder, Bipolar II Disorder (i.e. Recurrent MajorDepressive Episodes with Hypomanic Episodes) (296.89), CyclothymicDisorder (301.13) or Bipolar Disorder Not Otherwise Specified (296.80)).

In a still further embodiment, diseases or conditions that may bemediated by modulation of voltage gated sodium channels areNicotine-Related Disorders such as Nicotine Dependence (305.1), NicotineWithdrawal (292.0) or Nicotine-Related Disorder Not Otherwise Specified(292.9).

Compounds of the invention may also be useful in the treatment and/orprevention of disorders treatable and/or preventable withanti-convulsive agents, such as epilepsy including post-traumaticepilepsy, obsessive compulsive disorders (OCD), sleep disorders(including circadian rhythm disorders, insomnia & narcolepsy), tics(e.g. Giles de la Tourette's syndrome), ataxias, muscular rigidity(spasticity), and temporomandibular joint dysfunction.

Compounds of the invention may also be useful in the treatment ofbladder hyperrelexia following bladder inflammation.

Compounds of the invention may also be useful in the treatment ofneurodegenerative diseases and neurodegeneration such as dementia,particularly degenerative dementia (including senile dementia,Alzheimer's disease, Pick's disease, Huntington's chorea, Parkinson'sdisease and Creutzfeldt-Jakob disease, motor neuron disease); Thecompounds may also be useful for the treatment of amyotrophic lateralsclerosis (ALS) and neuroinflamation.

Compounds of the invention may also be useful in neuroprotection and inthe treatment of neurodegeneration following stroke, cardiac arrest,pulmonary bypass, traumatic brain injury, spinal cord injury or thelike.

Compounds of the invention may also be useful in the treatment oftinnitus, and as local anaesthetics.

The compounds of the invention may also be used in combination withother therapeutic agents. The invention thus provides, in a furtheraspect, a combination comprising a compound of the invention or apharmaceutically acceptable derivative thereof together with a furthertherapeutic agent.

When a compound of the invention or a pharmaceutically acceptablederivative thereof is used in combination with a second therapeuticagent active against the same disease state the dose of each compoundmay differ from that when the compound is used alone. Appropriate doseswill be readily appreciated by those skilled in the art. It will beappreciated that the amount of a compound of the invention required foruse in treatment will vary with the nature of the condition beingtreated and the age and the condition of the patient and will beultimately at the discretion of the attendant physician or veterinarian.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical formulation and thus pharmaceuticalformulations comprising a combination as defined above together with apharmaceutically acceptable carrier or excipient comprise a furtheraspect of the invention. The individual components of such combinationsmay be administered either sequentially or simultaneously in separate orcombined pharmaceutical formulations by any convenient route.

When administration is sequential, either the compound of the inventionor the second therapeutic agent may be administered first. Whenadministration is simultaneous, the combination may be administeredeither in the same or different pharmaceutical composition.

When combined in the same formulation it will be appreciated that thetwo compounds must be stable and compatible with each other and theother components of the formulation. When formulated separately they maybe provided in any convenient formulation, conveniently in such manneras are known for such compounds in the art.

When used in the treatment or prophylaxis of pain, the compound offormula (I) or a pharmaceutically acceptable salt thereof may be used incombination with other medicaments indicated to be useful in thetreatment or prophylaxis of pain of neuropathic origin includingneuralgias, neuritis and back pain, and inflammatory pain includingosteoarthritis, rheumatoid arthritis, acute inflammatory pain, back painand migraine. Such therapeutic agents include for example COX-2(cyclooxygenase-2) inhibitors, such as celecoxib, deracoxib, rofecoxib,valdecoxib, parecoxib, COX-189 or2-(4-ethoxy-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine(WO 99/012930); 5-lipoxygenase inhibitors; NSAIDs (non-steroidalanti-inflammatory drugs) such as diclofenac, indomethacin, nabumetone oribuprofen; bisphosphonates, leukotriene receptor antagonists; DMARDs(disease modifying anti-rheumatic drugs) such as methotrexate; adenosineAl receptor agonists; sodium channel blockers, such as lamotrigine; NMDA(N-methyl-D-aspartate) receptor modulators, such as glycine receptorantagonists or memantine; ligands for the α₂δ-subunit of voltage gatedcalcium channels, such as gabapentin, pregabalin and solzira; tricyclicantidepressants such as amitriptyline; neurone stabilising antiepilepticdrugs; cholinesterase inhibitors such as galantamine; mono-aminergicuptake inhibitors such as venlafaxine; opioid analgesics; localanaesthetics; 5HT₁ agonists, such as triptans, for example sumatriptan,naratriptan, zolmitriptan, eletriptan, frovatriptan, almotriptan orrizatriptan; nicotinic acetyl choline (nACh) receptor modulators;glutamate receptor modulators, for example modulators of the NR2Bsubtype; EP₄ receptor ligands; EP₂ receptor ligands; EP₃ receptorligands; EP₄ agonists and EP₂ agonists; EP₄ antagonists; EP₂ antagonistsand EP₃ antagonists; cannabinoid receptor ligands; bradykinin receptorligands; vanilloid receptor or Transient Receptor Potential (TRP)ligands; and purinergic receptor ligands, including antagonists at P2X₃,P2X_(2/3), P2X₄, P2X₇ or P2X_(4/7); KCNQ/Kv7 channel openers, such asretigabine; additional COX-2 inhibitors are disclosed in U.S. Pat. No.5,474,995, U.S. Pat. No. 5,633,272, U.S. Pat. No. 5,466,823, U.S. Pat.No. 6,310,099 and U.S. Pat. No. 6,291,523; and in WO 96/25405, WO97/38986, WO 98/03484, WO 97/14691, WO 99/12930, WO 00/26216, WO00/52008, WO 00/38311, WO 01/58881 and WO 02/18374.

The compounds of the invention may be used in combination with thefollowing agents to treat or prevent psychotic disorders: i)antipsychotics; ii) drugs for extrapyramidal side effects, for exampleanticholinergics (such as benztropine, biperiden, procyclidine andtrihexyphenidyl), antihistamines (such as diphenhydramine) anddopaminergics (such as amantadine); iii) antidepressants; iv)anxiolytics; and v) cognitive enhancers for example cholinesteraseinhibitors (such as tacrine, donepezil, rivastigmine and galantamine).

The compounds of the invention may be used in combination with thefollowing agents to treat or prevent psychotic disorders: i)antipsychotics; ii) drugs for extrapyramidal side effects, for exampleanticholinergics (such as benztropine, biperiden, procyclidine andtrihexyphenidyl), antihistamines (such as diphenhydramine) anddopaminergics (such as amantadine); iii) antidepressants; iv)anxiolytics; and v) cognitive enhancers for example cholinesteraseinhibitors (such as tacrine, donepezil, rivastigmine and galantamine).

The compounds of the invention may be used in combination withantidepressants to treat or prevent depression and mood disorders.

The compounds of the invention may be used in combination with thefollowing agents to treat or prevent bipolar disease: i) moodstabilisers; ii) antipsychotics; and iii) antidepressants.

The compounds of the invention may be used in combination with thefollowing agents to treat or prevent anxiety disorders: i) anxiolytics;and ii) antidepressants.

The compounds of the invention may be used in combination with thefollowing agents to improve nicotine withdrawal and reduce nicotinecraving: i) nicotine replacement therapy for example a sublingualformulation of nicotine beta-cyclodextrin and nicotine patches; and ii)bupropion.

The compounds of the invention may be used in combination with thefollowing agents to improve alcohol withdrawal and reduce alcoholcraving: i) NMDA receptor antagonists for example acamprosate; ii) GABAreceptor agonists for example tetrabamate; and iii) Opioid receptorantagonists for example naltrexone.

The compounds of the invention may be used in combination with thefollowing agents to improve opiate withdrawal and reduce opiate craving:i) opioid mu receptor agonist/opioid kappa receptor antagonist forexample buprenorphine; ii) opioid receptor antagonists for examplenaltrexone; and iii) vasodilatory antihypertensives for examplelofexidine.

The compounds of the invention may be used in combination with thefollowing agents to treat or prevent sleeping disorders: i)benzodiazepines for example temazepam, lormetazepam, estazolam andtriazolam; ii) non-benzodiazepine hypnotics for example zolpidem,zopiclone, zaleplon and indiplon; iii) barbiturates for exampleaprobarbital, butabarbital, pentobarbital, secobarbita andphenobarbital; iv) antidepressants; v) other sedative-hypnotics forexample chloral hydrate and chlormethiazole.

The compounds of the invention may be used in combination with thefollowing agents to treat anorexia: i) appetite stimulants for examplecyproheptidine; ii) antidepressants; iii) antipsychotics; iv) zinc; andv) premenstral agents for example pyridoxine and progesterones.

The compounds of the invention may be used in combination with thefollowing agents to treat or prevent bulimia: i) antidepressants; ii)opioid receptor antagonists; iii) antiemetics for example ondansetron;iv) testosterone receptor antagonists for example flutamide; v) moodstabilisers; vi) zinc; and vii) premenstral agents.

The compounds of the invention may be used in combination with thefollowing agents to treat or prevent autism: i) antipsychotics; ii)antidepressants; iii) anxiolytics; and iv) stimulants for examplemethylphenidate, amphetamine formulations and pemoline.

The compounds of the invention may be used in combination with thefollowing agents to treat or prevent ADHD: i) stimulants for examplemethylphenidate, amphetamine formulations and pemoline; and ii)non-stimulants for example norepinephrine reuptake inhibitors (such asatomoxetine), alpha 2 adrenoceptor agonists (such as clonidine),antidepressants, modafinil, and cholinesterase inhibitors (such asgalantamine and donezepil).

The compounds of the invention may be used in combination with thefollowing agents to treat personality disorders: i) antipsychotics; ii)antidepressants; iii) mood stabilisers; and iv) anxiolytics.

The compounds of the invention may be used in combination with thefollowing agents to treat or prevent male sexual dysfunction: i)phosphodiesterase V inhibitors, for example vardenafil and sildenafil;ii) dopamine agonists/dopamine transport inhibitors for exampleapomorphine and buproprion; iii) alpha adrenoceptor antagonists forexample phentolamine; iv) prostaglandin agonists for examplealprostadil; v) testosterone agonists such as testosterone; vi)serotonin transport inhibitors for example serotonin reuptakeinhibitors; v) noradrenaline transport inhibitors for example reboxetineand vii) 5-HT1A agonists, for example flibanserine.

The compounds of the invention may be used in combination with the sameagents specified for male sexual dysfunction to treat or prevent femalesexual dysfunction, and in addition an estrogen agonist such asestradiol.

Antipsychotic drugs include Typical Antipsychotics (for examplechlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine,prochlorperazine, trifluoperazine, thiothixine, haloperidol, molindoneand loxapine); and Atypical Antipsychotics (for example clozapine,olanzapine, risperidone, quetiapine, aripirazole, ziprasidone andamisulpride).

Antidepressant drugs include serotonin reuptake inhibitors (such ascitalopram, escitalopram, fluoxetine, paroxetine and sertraline); dualserotonin/noradrenaline reuptake inhibitors (such as venlafaxine,duloxetine and milnacipran); Noradrenaline reuptake inhibitors (such asreboxetine); tricyclic antidepressants (such as amitriptyline,clomipramine, imipramine, maprotiline, nortriptyline and trimipramine);monoamine oxidase inhibitors (such as isocarboxazide, moclobemide,phenelzine and tranylcypromine); and others (such as bupropion,mianserin, mirtazapine, nefazodone and trazodone).

Mood stabiliser drugs include lithium, sodium valproate/valproicacid/divalproex, carbamazepine, lamotrigine, gabapentin, topiramate andtiagabine.

Anxiolytics include benzodiazepines such as alprazolam and lorazepam.

It will be appreciated that references herein to “treatment” extend toprophylaxis, prevention of recurrence and suppression or amelioration ofsymptoms (whether mild, moderate or severe) as well as the treatment ofestablished conditions.

The compound of the invention may be administered as the raw chemicalbut the active ingredient is preferably presented as a pharmaceuticalformulation.

According to a further aspect, the invention provides a pharmaceuticalcomposition comprising a compound of the invention, in association withone or more pharmaceutically acceptable carrier(s), diluents(s) and/orexcipient(s). The carrier, diluent and/or excipient must be “acceptable”in the sense of being compatible with the other ingredients of thecomposition and not deleterious to the recipient thereof.

The compounds of the invention may be administered in conventionaldosage forms prepared by combining a compound of the invention withstandard pharmaceutical carriers or diluents according to conventionalprocedures well known in the art. These procedures may involve mixing,granulating and compressing or dissolving the ingredients as appropriateto the desired preparation.

The pharmaceutical compositions of the invention may be formulated foradministration by any route, and include those in a form adapted fororal, topical or parenteral administration to mammals including humans.

The compositions may be in the form of tablets, capsules, powders,granules, lozenges, creams or liquid preparations, such as oral orsterile parenteral solutions or suspensions.

The topical formulations of the present invention may be presented as,for instance, ointments, creams or lotions, eye ointments and eye or eardrops, impregnated dressings and aerosols, and may contain appropriateconventional additives such as preservatives, solvents to assist drugpenetration and emollients in ointments and creams.

The formulations may also contain compatible conventional carriers, suchas cream or ointment bases and ethanol or oleyl alcohol for lotions.Such carriers may be present as from about 1% up to about 98% of theformulation. More usually they will form up to about 80% of theformulation.

Tablets and capsules for oral administration may be in unit dosepresentation form, and may contain conventional excipients such asbinding agents, for example syrup, acacia, gelatine, sorbitol,tragacanth, or polyvinylpyrrolidone; fillers, for example lactose,sugar, maize-starch, calcium phosphate, sorbitol or glycine; tablettinglubricants, for example magnesium stearate, talc, polyethylene glycol orsilica; disintegrants, for example potato starch; or acceptable wettingagents such as sodium lauryl sulphate. The tablets may be coatedaccording to methods well known in normal pharmaceutical practice. Oralliquid preparations may be in the form of, for example, aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives, such as suspending agents, for example sorbitol,methyl cellulose, glucose syrup, gelatine, hydroxyethyl cellulose,carboxymethyl cellulose, aluminium stearate gel or hydrogenated ediblefats, emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample almond oil, oily esters such as glycerine, propylene glycol, orethyl alcohol; preservatives, for example methyl or propylp-hydroxybenzoate or sorbic acid, and, if desired, conventionalflavouring or colouring agents.

Suppositories will contain conventional suppository bases, e.g.cocoa-butter or other glyceride.

For parenteral administration, fluid unit dosage forms are preparedutilising the compound and a sterile vehicle, water being preferred. Thecompound, depending on the vehicle and concentration used, can be eithersuspended or dissolved in the vehicle. In preparing solutions thecompound can be dissolved in water for injection and filter-sterilisedbefore filling into a suitable vial or ampoule and sealing.

Advantageously, agents such as a local anaesthetic, preservative andbuffering agents can be dissolved in the vehicle. To enhance thestability, the composition can be frozen after filling into the vial andthe water removed under vacuum. The dry lyophilised powder is thensealed in the vial and an accompanying vial of water for injection maybe supplied to reconstitute the liquid prior to use. Parenteralsuspensions are prepared in substantially the same manner except thatthe compound is suspended in the vehicle instead of being dissolved andsterilisation cannot be accomplished by filtration. The compound can besterilised by exposure to ethylene oxide before suspending in thesterile vehicle. Advantageously, a surfactant or wetting agent isincluded in the composition to facilitate uniform distribution of thecompound.

The compositions may contain from 0.1% by weight, for example from10-60% by weight, of the active material, depending on the method ofadministration. Where the compositions comprise dosage units, each unitwill for example contain from 5-1000 mg of the active ingredient. Thedosage as employed for adult human treatment may range from 10 to 3000mg per day depending on the route and frequency of administration. Fororal administration a typical dose may be in the range of 50 to 1500 mgper day, for example 120 to 1000 mg per day.

It will be recognised by one of skill in the art that the optimalquantity and spacing of individual dosages of a compound of theinvention will be determined by the nature and extent of the conditionbeing treated, the form, route and site of administration, and theparticular mammal being treated, and that such optimums can bedetermined by conventional techniques. It will also be appreciated byone of skill in the art that the optimal course of treatment, i.e., thenumber of doses of a compound of the invention given per day for adefined number of days, can be ascertained by those skilled in the artusing conventional course of treatment determination tests.

All publications, including, but not limited to, patents and patentapplications cited in this specification, are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

It will be appreciated that the invention includes the following furtheraspects. The embodiments described for the first aspect similarly applyto these further aspects. The diseases and conditions described aboveextend, where appropriate, to these further aspects:

-   -   i) A compound of the invention for use in treating or preventing        a disease or condition mediated by modulation of voltage-gated        sodium channels.    -   ii) A method of treatment or prevention of a disease or        condition mediated by modulation of voltage-gated sodium        channels in a mammal comprising administering an effective        amount of a compound of the invention.    -   iii) Use of a compound of the invention in the manufacture of a        medicament to treat or prevent a disease or condition mediated        by modulation of voltage-gated sodium channels.    -   iv) Use of a compound of the invention to treat or prevent a        disease or condition mediated by modulation of voltage-gated        sodium channels.

EXAMPLES

The invention is illustrated by the Examples described below.

In the procedures that follow, after each starting material, referenceto a Description or Example by number is typically provided. This isprovided merely for assistance to the skilled chemist. The startingmaterial may not necessarily have been prepared from the batch referredto.

Where reference is made to the use of a “similar” procedure, as will beappreciated by those skilled in the art, such a procedure may involveminor variation, for example reaction temperature, reagent/solventamount, reaction time, work-up conditions or chromatographicpurification conditions.

The absolute configuration of the stereocentres within the spiro fusedcompounds prepared from achiral starting materials and resolved by useof chiral chromatography have been assigned using a combination ofoptical rotation and NMR spectroscopy (for determining the relativestereochemistry of adjacent stereocentres) and relating these to chiralintermediates and final compounds which have had their absoluteconfigurations determined by single crystal X-ray crystallography. Itwill be appreciated that some uncertainty exists relating to theabsolute configurations referred to herein which have been basedprimarily on inferred configurations. It will be apparent to the skilledperson that absolute configurations can only be definitivelycharacterised by specific analytical determinations, such as X-raycrystallography.

Compounds are named using ACD/Name PRO 6.02 chemical naming software(Advanced Chemistry Development Inc., Toronto, Ontario, M5H2L3, Canada),or using Lexichem's automatic chemical naming software Version 2.0.1(OpenEye Scientific Software Inc. Santa Fe, N.Mex., USA).

Proton Magnetic Resonance (NMR) spectra are typically recorded on aBruker instruments at 300, 400 or 500 MHz. Chemical shifts are reportedin ppm (δ) using the residual solvent line as internal standard.Splitting patterns are designated as s, singlet; d, doublet; t, triplet;q, quartet; m, multiplet; br, broad. The NMR spectra were recorded at atemperature ranging from 25 to 90° C. When more than one conformer wasdetected the chemical shifts for the most abundant one is reported.

LC-MS Data (LC-MS) is typically generated on an Waters ZQ MassSpectrometer, operating in switched ES+ and ES− ionization modes coupledto an Agilent 1100 Series HPLC system with in line Aglient 1100 UV-DADand Sedere SEDEX 75 ELSD Detection. Instrument control and dataacquisition is mediated through the Waters MassLynx—OpenLynx softwaresuite. Separation was performed on a Waters SunFire C18 (30×4.6 mm, 3.5μm) column Flow Rate: 3.0 mL/min. column temperature 30° C. InjectionVolume: 5.0 μL. Mobile phase [A]: 3:97:0.05 (v/v/v) Acetonitrile: Water:Formic Acid. Mobile Phase [B]: 97:3:0.05 (v/v/v) Acetonitrile: Water:Formic Acid. Gradient: 97% [A] 3% [B] for 0.1 min. Ramp to 3% [A] 97%[B] at 4.0 min. Hold at 97% [B] to 5 min. Return to 97% [A] at 6 min.Detector parameters: UV -DAD: Range 190 to 450 nm, Interval 2 nm,Threshold 0.1 mAU. ELSD: Temperature 40° C., Range 8. Mass Spectrometer:ES+: Mass Range 125 to 625 in 0.50 sec. lnterscan delay 0.25 sec.Capillary 4.0 kV. ES−: Mass Range 125 to 625 in 0.50 sec. lnterscandelay 0.25 sec. Capillary 3.0 kV.

In the mass spectra only one peak in the molecular ion cluster isusually reported.

Chiral chromatography was typically performed using a ChiralPak™ AD-H orIA column from Daicel® using heptane/ethanol or heptane/ethanol/methanolmixtures as eluent. Analytical chiral HPLC was carried out either on anAgilent 1100 series HPLC system or on a Gilson HPLC system using a250×4.6 mm column and a flow rate of 1 ml/min. Preparative chiral HPLCwas carried out using a Gilson preparative HPLC system on a 250×19 mmsemi-preparative column with a flow rate of 18 ml/min.

Flash silica gel chromatography was carried out on silica gel 230-400mesh (supplied by Merck AG Darmstadt, Germany) or over pre-packedBiotage silica or NH silica cartridges.

Optical rotations were measured using an Optical Activity Ltd AA-10automatic polarimeter (Cambridge, UK) using a cell of 10 cm path lengthand in chloroform solution unless otherwise indicated.

SCX cartridges are ion exchange solid phase extraction columns suppliedby Varian. The eluent used with SCX cartridges is methanol followed by0.2-2.0 M ammonia solution in methanol.

In most preparations, purification was performed using Biotage automaticflash chromatography (SP4 or Isolera) systems.

The following abbreviations are used herein:

AD-H ChiralPak AD-H semipreparative column

Boc tertButyloxycarbonyl

CHCl₃ Chloroform

DCM Dichloromethane

DCE 1,2-Dichloroethane

DME Dimethoxyethane

EtOAc Ethyl Acetate

Et₂O Ether

HCl Hydrochloric Acid

HPLC High-performance liquid chromatography

IPA Isopropyl alcohol

K₂CO₃ Potassium carbonate

LC-MS Liquid chromatography-Mass spectrometry

MeCN Acetonitrile

MeOMethanol

MgSO₄ Magnesium sulfate

Na₂CO₃ Sodium carbonate

NMR Nuclear Magnetic Resonance

Na₂SO₄ Sodium sulfate

PdCl₂(Ph₃P)₂ Bis(triphenylphosphine)palladium(II) chloride

THF Tetrahydrofuran

PREPARATION OF INTERMEDIATES

Description 1

3-(Benzhydrylidene-amino)-1-methyl-pyrrolidin-2-one (D1)

Method 1: Benzophenone imine [CAS: 1013-88-3] (16.67 g, 91.98 mmol) wasadded dropwise to a solution of 3-amino-1-methylpyrrolidine-2-one [CAS119329-48-5] (10 g, 87.60 mmol) in DCE (100 mL) under N₂ and thereaction was heated at reflux for 18 hours. The solvent was evaporatedto afford an amber oil. This was purified using flash silica in a largesinter funnel, eluting with 4:1 to 3:7 i-hexane:EtOAc. An incompleteseparation was achieved.3-(Benzhydrylidene-amino)-1-methyl-pyrrolidin-2-one (D1) was isolated(25 g) with approximately 11% of an impurity present, but was used inthe next step without further purification;

300 MHz NMR δ_(H) (CDCl₃) 2.15-2.49 (2H, m), 2.90 (3H, s), 3.26-3.34(1H, abq), 3.52 (1H, dt), 4.23 (1H, t), 7.30-7.49 (8H, m), 7.63-7.67(2H, m).

Method 2: Benzophenone imine (200.04 g,1103.8 mmol) was added dropwiseover 20 minutes to a stirred solution of3-amino-1-methylpyrrolidine-2-one (120 g, 1051.2 mmol) in DCE (1000 mL)at ambient temp under nitrogen in a 2 L flask fitted with a magneticstirrer bar. The reagent was washed with further DCE (100 mL). Thestirred solution was heated at reflux on a heat-on block at a block tempof 95° C. for 7 h, using a N₂ bubbler with exhaled gas passing through asafety trap then into 2 L of water via an upturned funnel (for scrubbingNH₃ gas, estimated to be approx 23 L). The reaction was left to stand atambient temp overnight under N₂. The mixture was evaporated to a thick,off-white oil. To this was added Et₂O (700 ml) and to this stirredsolution, as it began to crystallize, was added iso-hexane (700 ml) over2 minutes. The mixture was stirred for 1 h then filtered under suctionand washed with Et₂O/iso-hexane (1:1) (500 ml). The white solid wasdried at 35° C. under vacuum for 3 h to afford3-(benzhydrylidene-amino)-1-methyl-pyrrolidin-2-one (D1) (259.4 g,88.6%). The NMR was consistent with pure material.

Description 2

3-(Benzhydrylidene-amino)-1-methyl-3-prop-2-ynyl-pyrrolidin-2-one (D2)

Method 1: Potassium tert-butoxide 1.7M in THF (32.8 mL, 55.76 mmol) wasadded dropwise over a period of 80 minutes (by syringe pump) to asolution of the 3-(benzhydrylidene-amino)-1-methyl-pyrrolidin-2-one(14.11 g, 50.692 mmol) (which may be prepared as described inDescription 1) and propargyl bromide (6.78 mL, 60.83 mmol) in THF (250mL) at 0° C. under nitrogen. The reaction was stirred for 2 hours.Additional KO^(t)Bu (5 ml) was added dropwise and stirring was continuedfor 15 mins. The reaction was quenched by the addition of satd. aq.NaHCO₃ and diluted with EtOAc. The phases were separated, the organiclayer was dried (Na₂SO₄) and the solvent evaporated to afford a crudebrown oil which solidified on standing. This waxy-solid was suspended inIPA (approx. 30 ml) and stirred for 1 hr. The solid was filtered off,washed with a little IPA to afford3-(benzhydrylidene-amino)-1-methyl-3-prop-2-ynyl-pyrrolidin-2-one (D2)as a light brown solid (6.26 g);

300 MHz NMR δ_(H) (CDCl₃) 1.95 (1H, t), 2.14-2.24 (1H, m), 2.44 (3H, s),2.45-2.64 (2H, m), 2.94 (2H, t), 3.11 (1H, dt), 7.23-7.48 (8H, m),7.55-7.59 (2H, m).

Method 2: Potassium tert-butoxide 1.7M in THF (602.08 mL, 1023.5 mmol)was added dropwise over a period of 2.5 h to a stirred solution of3-(benzhydrylidene-amino)-1-methyl-pyrrolidin-2-one (259 g, 930.48mmol)) (which may be prepared as described in Description 1) and 80%solution propargyl bromide in toluene (124.37 mL, 1116.6 mmol) in3A-molecular-sieve-dried reagent grade THF (1900 mL) at −65° C. undernitrogen, in a 5 L flask equipped with an overhead stirrer. After theaddition was complete, the mixture was stirred at −65° C. for a further1 h. The cooling bath was removed and a saturated solution of NaHCO₃(140 ml) was added over 1 minute (at −60° C.). After a further 5 minsmore sat NaHCO₃ solution (1.4 L) was added followed by Et₂O (1.4 L). Themixture was stirred for 1 h then transferred to a separating funnel andwater (1.4 L) was added to dissolve all solids. The layers wereseparated and the aqueous further extracted with Et₂O (2×1 L). Thecombined organic extracts were re-washed with sat. brine (700 ml),diluted with water (700 ml). The organic layer was dried (MgSO₄) andevaporated to a volume of approx. 500-600 ml whereupon crystallizationstarted to occur. To this stirred mixture was then added iso-hexane (1.6L). After standing for 15 mins the cream solid was filtered undersuction and washed with iso-hexane (500 ml) and dried at 50° C. undervacuum for 5 h. This afforded3-(benzhydrylidene-amino)-1-methyl-3-prop-2-ynyl-pyrrolidin-2-one (D2)(274 g, 93%). This was pure by NMR but contains some additional water.

Description 3 (3S)-3-Amino-1-methyl-3-prop-2-ynyl-pyrrolidin-2-one (D3S)and (3R)-3-Amino-1-methyl-3-prop-2-ynyl-pyrrolidin-2-one (D3R)

Method 1: Citric acid monohydrate (10.39 g, 49.46 mmol) was added to asolution of3-(benzhydrylidene-amino)-1-methyl-3-prop-2-ynyl-pyrrolidin-2-one (6.26g, 19.79 mmol) (which may be prepared as described in Description 2) inTHF (150 mL) and the reaction was stirred at room temperature for 18hours. A colourless solid precipitated out. The solvent was evaporatedto give a gummy white solid. This was trituated with Et₂O and the solidwas washed with further Et₂O. The solid was suspended in water/MeOH andpurified by SCX (70 g Silca), eluting with water/MeOH, MeOH and finally0.5M NH₃ in MeOH. Fractions containing product were evaporated to afford3-amino-1-methyl-3-prop-2-ynyl-pyrrolidin-2-one (3.23 g, 21.223 mmol) asa pale yellow oil;

300 MHz NMR δ_(H) (CDCl₃) 1.65 (2H, br.s), 1.94-2.05 (2H, m), 2.31-2.39(1H, m), 2.41-2.55 (2H, m), 2.89 (3H, Me), 3.33-3.39 (2H, m).

Method 2: To a stirred solution of3-(benzhydrylideneamino)-1-methyl-3-prop-2-ynyl-pyrrolidin-2-one (274 g,865.99 mmol) (which may be prepared as described in Description 2) in a5L flask equipped with an overhead stirrer, in THF (2.7 L) was addedcitric acid monohydrate (363.96 g, 1732 mmol) in one portion. Thesolution was stirred at room temperature for 18 h, giving a thick whiteprecipitate with some sticky solid adhering to the sides of the flask.This sticky solid was loosened with a spatula, then diethyl ether (1.3L) was added and rapid stirring was continued for a further 1 h. Thesolid was then filtered under suction and washed efficiently with Et₂O(2×1 L) and dried at 50° C. under vacuum for 3 hours. This produced 268gof material. This was recrystallized from hot MeOH (1.9 L); hot solutionwas filtered under suction to give a clear pale yellow solution. Thesolution was left to stand for 1 h and Et₂O (3 L) was added withstirring. After standing for a further 1 h, the mixture was filtered andwashed with MeOH:Et₂O (1:2) (1 L) and the solid pressed dry and furtherdried at 50° C. under vacuum for 6 hours to afford 312 g of the citratesalt, contaminated with methanol. In a separate container, Ambersep 900(OH) ion exchange resin (2.31 kg) was stirred for 5 minutes with MeOH (2L) to pre-wash the resin. The suspended resin was filtered under suctionand the moist pre-washed resin was added to a stirred suspension of thepreviously prepared citrate salt in methanol (3 L) in a 10 L vesselequipped with an overhead stirrer. The mixture was stirred for a totalof 1.5 h at ambient temp then filtered under suction. The filtered resinwas washed with MeOH (2×1.5 L). The filtrate and washings wereevaporated in vacuo to an oil which was redissolved in DCM (1.5 L) anddried (Na₂SO₄), filtered, evaporated to a pale yellow oil, which wasdried at RT overnight to give3-amino-1-methyl-3-prop-2-ynyl-pyrrolidin-2-one (106.9 g, 79.9%). NMRshowed this to be pure material identical to that prepared inDescription 3, Method 1. A portion of this material (1.75 g, 11.5 mmol)was separated on chiral HPLC using a semi-prep AD-H column, eluting with20% EtOH/heptane at 18 ml/min. Peaks were identifed at 215 nm:

(3S)-3-amino-1-methyl-3-prop-2-ynyl-pyrrolidin-2-one D3S 549 mgretention time=13.7 mins; Optical rotation α[D/22]=−81.0 (c=0.975,CHCl₃).

(3R)-3-amino-1-methyl-3-prop-2-ynyl-pyrrolidin-2-one D3R 407 mgretention time=17.9 mins; Optical rotation α[D/22]=+78.8 (c =0.965,CHCl₃). Method 3: A controlled lab reactor with heater/cooler jacket andan overhead paddle-stirrer was charged with IPA (2250 mL) and(2S)-2-(6-methoxy-2-naphthyl)propanoic acid (84.72 g, 367.92 mmol) wasadded. The suspension was stirred and warmed to 75° C. giving asolution. A solution of 3-amino-1-methyl-3-prop-2-ynyl-pyrrolidin-2-one(which may be prepared as described in Description 3, Method 2) (55.99g, 367.92 mmol) in IPA (1100 mL) was then added dropwise over 1.5 hours.In a cooling process, the reaction mixture was stirred at 75° C. for 1hr then cooled to 55° C. over 1 hr. The reaction was seeded with pure(S) isomer salt at every 1 degree drop in temperature until the seedremained out of solution (ca. 71° C.). The reaction mixture crystallisedand was stirred at 55° C. for 1 hr. The mixture was then cooled to 40°C. over approximately 20 minutes and filtered under suction into apre-warmed filter funnel over a fast filter paper. The vessel was rinsedout with IPA (600 mL) pre-warmed to 40° C. and this was used to wash thecollected solids. The solids were dried under suction until no moresolvent came out and then were dried in a vacuum oven at 50° C. to givea white solid, 59.37 g(3S)-1-methyl-2-oxo-3-prop-2-ynyl-pyrrolidin-3-yl]ammonium(2S)-2-(6-methoxy-2-naphthyl)propanoate. A portion of this material wasremoved and dissolved in methanol, passed down an SCX column, washedwith methanol and then eluted with 0.5M ammonia in methanol. The ammoniaeluent was evaporated to a pale yellow gum, which was analysed by chiralHPLC (20:80 EtOH:heptane, IA column) showing S-isomer 99.5% and R-isomer0.5%. Ambersep 900-OH (500 g) was stirred in methanol (1000 mL) for 5minutes, then filtered and dried under suction until no more liquid cameout. The washed resin was added to a stirred suspension of S-isomer salt(59.37 g, 155.24 mmol) in methanol (1000 mL). The mixture was stirredfor 1 hr, then filtered. The resin was resuspended in methanol (1000 mL)and stirred for an hour and then filtered. The combined filtrates wereevaporated to give a slightly cloudy yellow oil. The oil was dissolvedin dichloromethane (ca. 200 mL) and dried over magnesium sulphate,filtered and evaporated to give a clear yellow oil(3S)-3-amino-1-methyl-3-prop-2-ynyl-pyrrolidin-2-one (D3S) (22.729 g).This material was characterised as identical to that prepared by chiralchromatography in

Method 2.

Method 4: Enriched recrystallisation mother liquors containing, forexample, a 91:9 ratio of(3R)-3-amino-1-methyl-3-prop-2-ynyl-pyrrolidin-2-one and its (3S)enantiomer, (27 g) (which may be obtained from the fractionalcrystalisation procedure described in Description 3 Method 3) wereevaporated and dissolved in acetonitrile at 30±5° C. The reaction masswas heated to 70±5° C. and stirred for 10 minutes then slowly cooled to40±2° C. A seed of the R-amine-(2S)-2-(6-methoxy-2-naphthyl)propanoicacid was introduced and the reaction mixture maintained at 40±2° C. for1 hr. The reaction mass was cooled to 30±5° C. and filtered. Theisolated salt was washed with acetonitrile and dried under vacuum at47.5±2.5° C. for 6±1 hours to give 18.2 g of the salt with a 99.8%enantiomeric excess of the R isomer. The material was then converted tothe free base form as described for the S-enantiomer in Method 3 to givethe title compound (D3R). This material was characterised as identicalto that prepared by chiral chromatography in Method 2.

Description 4

tert-ButylN-[(3S)-1-methyl-2-oxo-3-prop-2-ynyl-pyrrolidin-3-yl]carbamate (D4)

Method 1: Boc₂O (944.75 mg, 4.33 mmol) was added to a solution of(3S)-3-amino-1-methyl-3-prop-2-ynyl-pyrrolidin-2-one (which may beprepared as described in Description 3) (549 mg, 3.61 mmol) in DCM (20mL) at 20° C. and the reaction was stirred for 18 hrs. The solvent wasevaporated and the residue purified on a Biotage Isolera with a 25g SNAPcartridge, eluting with 0 to 100% EtOAc/i-hexane to afford tert-butylN-[(3S)-1-methyl-2-oxo-3-prop-2-ynyl-pyrrolidin-3-yl]carbamate (D4) (849mg, 3.365 mmol, 93.3% yield) as a pale yellow solid.

Method 2: Boc₂O (2.77 g, 12.69 mmol) was added to a solution of(3S)-3-amino-1-methyl-3-prop-2-ynyl-pyrrolidin-2-one (which may beprepared as described in Description 3) (1.61 g, 10.58 mmol) in DCM (40mL) at 20° C. and the reaction was stirred for 18 h. The reaction waswarmed to 40° C. and stirred for a further 3 days. The solvent wasevaporated and the residue purified using a Biotage Isolera with a 25gSNAP cartridge eluting with 0 to 80% EtOAc/i-hexane to afford tert-butylN-[(3S)-1-methyl-2-oxo-3-prop-2-ynyl-pyrrolidin-3-yl]carbamate (D4)(2.52 g, 9.9877 mmol, 94.4% yield) as a pale yellow solid; 300 MHz NMRδ_(H) (CDCl₃) 1.45 (9H, s), 2.02 (1H, t), 2.48-2.59 (3H, m), 2.27-2.35(1H, br.m), 2.92 (3H, s), 2.38-2.44 (2H, m), 5.23 (1H, br.s);

Optical rotation α[D/22]=−2 (c=1.01, CHCl₃).

Method 3: To a solution of(3S)-3-amino-1-methyl-3-prop-2-ynyl-pyrrolidin-2-one (which may beprepared as described in Description 3) (72.66 g, 477.4 mmol) in DCM(1000 mL) was added a solution of Boc₂O (125.03 g, 572.88 mmol) in DCM(700 mL) in one portion. The reaction was then stirred at 40° C. (bathtemp. not internal temp.) over 5 hrs, then at room temperature over theweekend. The reaction was concentrated in vacuo, and the residue wassuspended in a mixture of Et₂O and isohexane (1:1, 250 mL) and stirredfor 30 minutes. The suspension was filtered, and the solid was washedwith a mixture of Et₂O and isohexane (1:1, 250 mL), followed byisohexane (3×250 mL). The solid was then dried in a vacuum oven for 2hours (40° C.) to give a white solid, tert-butylN-[(3S)-1-methyl-2-oxo-3-prop-2-ynyl-pyrrolidin-3-yl]carbamate (D4)(99.25 g);

300 MHz NMR δ_(H) (CDCl₃) 1.43 (9H, s), 2.01 (1H, app.t), 2.45-2.59 (3H,m), 2.78, 2.82 (1H, 2 x br.s), 2.81 (3H, s), 3.35-3.45 (2H, m), 5.23(1H, br.s).

A second crop was isolated from the filtrate to give a further batch,5.535 g of similar purity.

Description 5

2-Chloro-4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidine (D5)

Method 1: To a solution of 2,4-dichloro-6-methyl-pyrimidine (5 g, 30.67mmol) in 1,2-dimethoxyethane (35 mL) and water (25 mL) was added sodiumcarbonate (9.75 g, 92.03 mmol), and 4-(trifluoromethyl)-phenylboronicacid (5.53 g, 29.14 mmol). This was degassed with nitrogen for 5minutes. The bis(triphenylphosphine)palladium (II) dichloride (1.08 g,1.53 mmol) was then added and the reaction was heated to 90° C.overnight. The solvent was evaporated and the residue was partitionedbetween water (300 mL) and EtOAc (300 mL). The organics were washed withbrine (100 mL), dried over MgSO₄ and concentrated in vacuo to afford ayellow oil. The material was purified using a Biotage SP4, 0 to 50%i-hexane/EtOAc and the fractions containing the lower (major) spot werecollected and the solvent evaporated to afford the2-chloro-4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidine (D5) (4.65 g,17.06 mmol, 55.6% yield) as a colourless solid. 300 MHz NMR δ_(H)(CDCl₃) 2.65 (3H, s), 7.57 (1H, s), 7.79 (2H, d), 8.21 (2H, d).

Method 2: To a solution of 4-(trifluoromethyl)phenylboronic acid (116.52g, 613.5 mmol) in 1,2-dimethoxyethane (1200 mL) was added2,4-dichloro-6-methylpyrimidine (100 g, 613.5 mmol). To this stirringsolution was added a solution of sodium carbonate (195.07 g, 1840.5mmol) dissolved in water (600 mL) giving some precipitation of the baseand then bis(triphenylphosphine)palladium (II) dichloride (2.15 g, 3.07mmol). The mixture was brought to 50° C. over about 1 hr then stirred atthis temperature overnight. The reaction mixture cooled to approx. 30°C., filtered and washed with DCM (approx. 500 mL). The filtrate wasevaporated to remove the bulk of the organic solvents. To the residueswas added DCM (250 mL) and the phases were separated. The aqueous phasewas extracted with DCM (2×250 mL) and the combined extracts were washedwith brine (250 mL), dried over magnesium sulphate, filtered andevaporated to a brown gummy solid. The solid was stirred in iso-hexane(150 mL) at 60° C. until the solid had dissolved. The heat was turnedoff and the flask allowed to cool in the heat-on block naturally. Whenthe solution was at 30° C. seed crystals were added causing immediatecrystallisation. The mixture was stood overnight then the crystallinematerial was crushed and filtered. The solids were washed with coldiso-hexane (2×50 mL) and dried to give the title compound (D5) as aslightly sticky tan solid, (96.17 g) consistent by NMR with thatprepared by Method 1.

Description 6

2-Iodo-4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidine (D6)

Method 1: Hydroiodic acid (57% in water, 9.68 mL, 73.41 mmol) was addedportionwise to 2-chloro-4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidine(which may be prepared as described in Description 5) (1.38 g, 5.06mmol) in DCM (30 mL) at 20° C. and the dark mixture was stirred for 18hrs. The mixture was quenched by the addition of sat. aq. K₂CO₃ (care:gas evolved). After basification, satd. aq. sodium metabisulphite wasadded and stirring was continued for 5 mins. The mixture was dilutedwith further DCM and the phases were separated. The organic layer wasdried (Na₂SO₄) and the solvent evaporated to afford2-iodo-4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidine (D6) (1.58 g,4.34 mmol, 85.7% yield) a yellow solid, containing about 20% of thereduced H-compound.

300 MHz NMR δ_(H) (CDCl₃) 2.59 (3H, s), 7.58 (1H, s), 7.77 (2H, d), 8.17(2H, d)

Method 2: To a solution of2-chloro-4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidine (which may beprepared as described in Description 5) (167.5 g, 614.34 mmol) in DCM(1325 mL) was added HI (57% in water) (405.23 mL, 3071.7 mmol) dropwise.The reaction was then stirred at room temperature overnight. AdditionalDCM (500 mL) was added, and the reaction was filtered. The solid wasdried then transferred into a beaker containing water (1 L) and EtOAc(1.25 L). The aqueous was basified to pH 10 with K₂CO₃, and the layerswere stirred until all the solid dissolved. Sodium metabisulfite (8.75g) was added and the layers were stirred until all solid dissolved. Thelayers were separated, and the aqueous was re-extracted with EtOAc (200mL). The combined organics were then dried over MgSO₄, filtered andconcentrated in vacuo to give the title material (D6) (205.68 g, 564.9mmol, 92% yield) as a pale orange solid. NMR indicated this was >95%pure.

Description 7

tert-ButylN-[(3S)-1-methyl-3-[3-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]prop-2-ynyl]-2-oxo-pyrrolidin-3-yl]carbamate(D7)

Method 1: Copper Iodide (149.46 mg, 0.7800 mmol), followed byPdCl₂(Ph₃P)₂ (275.41 mg, 0.3900 mmol) was added portionwise to asolution of 2-iodo-4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidine (4g, 10.99 mmol) (which may be prepared as described in Description 6),tert-butylN-[(3S)-1-methyl-2-oxo-3-prop-2-ynyl-pyrrolidin-3-yl]carbamate (1.98 g,7.85 mmol) (which may be prepared as described in Description 4) andEt₂NH (4.06 mL, 39.24 mmol) in THF (50 mL) under N₂ and the reaction wasstirred at 20° C. for 18 hrs. The solvent was evaporated and the residuewas suspended in EtOAc and washed with water/sat. aq. NaHCO₃. Theorganics were collected, dried (Na₂SO₄) and the solvent evaporated toafford a brown oil. This was purified using a Biotage SP4, with a 100 gSNAP cartridge, eluting with 50 to 100% EtOAc/i-hexane to affordtert-butylN-[(3S)-1-methyl-3-[3-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]prop-2-ynyl]-2-oxo-pyrrolidin-3-yl]carbamate(D7) (4.09 g, 8.3726 mmol) as a pale yellow foam;

300 MHz NMR δ_(H) (CDCl₃) 1.46 (9H, s), 2.5-2.75 (2H, m), 2.62 (3H, s),2.79-2.85 (1H, br.d), 2.98 (3H, s), 3.13-3.19 (1H, br.d), 3.40-3.47 (1H,br.t), 3.63-3.72 (1H, m), 5.35 (1H, br.s), 7.53, 1H, s), 7.78 (2H, d),8.19 (2H, d).

Method 2: In a 5 L three-necked flask with overhead paddle stirrer and anitrogen inlet. tert-butylN-[(3S)-1-methyl-2-oxo-3-prop-2-ynyl-pyrrolidin-3-yl]carbamate (whichmay be prepared as described in Description 4) (104.79 g, 415.32 mmol)was suspended in tert-Butyl methyl ether (2100 mL).2-Iodo-4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidine (which may beprepared as described in Description 6) (166.34 g, 456.85 mmol) wasadded followed by diisopropylamine (174.63 mL, 1246 mmol) and themixture was stirred over 20mins. To the suspension was added copperiodide (1.58 g, 8.31 mmol) followed by bis(triphenyl-phosphine)palladium(II) dichloride (2.92 g, 4.15 mmol) and the mixture was stirred at roomtemperature for 3 hours. Water (1000 mL) was added and the mixturestirred for 30 mins. The phases were separated and the organic phase,washed with water (2×500 mL), dried over magnesium sulphate, filteredand evaporated to a tan foam, 230 g. The material was purified in threebatches of approximately 75 g by column chromatography using an 800 g(Biotage 75L) column and eluting with a gradient of acetone iniso-hexane. This gave the title compound (D7) (179.3 g) in good purityby NMR and consistent spectroscopically with that produced by Method 1.

Description 8

(3S)-3-Amino-1-methyl-3-[3-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]prop-2-ynyl]pyrrolidin-2-one(D8)

Method 1: Trifluoroacetic acid (5 mL, 67.31 mmol) was added to asolution of tert-butylN-[3S)-1-methyl-3-[3-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]prop-2-ynyl]-2-oxo-pyrrolidin-3-yl]carbamate(3.83 g, 7.84 mmol) (which may be prepared as described in Description7) in DCM (50 mL) at 20° C. and the reaction was stirred overnight. Thereaction was concentrated and a further portion of trifluoroacetic acid(2 ml) added. Stirring was continued for 3 hrs then solid K₂CO₃ wasadded (care: gas evolved) and the mixture was diluted with water. Thephases were separated and the organic layer was dried (Na₂SO₄). Thesolvent was evaporated to give(3S)-3-amino-1-methyl-3-[3-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]prop-2-ynyl]pyrrolidin-2-one(D8) (2.71 g, 6.9775 mmol, 89% yield) as a yellow oil;

300 MHz NMR δ_(H) (CDCl₃) 1.95 (2H, br.s), 2.07-2.17 (1H, m), 2.44-2.53(1H, m), 2.63 (3H, s), 2.72-2.88 (2H, abq), 2.94 (3H, s), 3.38-3.53 (2H,m), 7.53 (1H, s), 7.78 (2H, d), 8.20 (2H, d).

Method 2: To a solution of tert-butylN-[(3S)-1-methyl-3-[3-[4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidin-2-yl]prop-2-ynyl]-2-oxo-pyrrolidin-3-yl]carbamate(which may be prepared as described in Description 7) (99.5 g, 203.68mmol) in 1,4-dioxane (750 mL) cooled with an ice/water bath to aninternal temperature of 15° C. was added conc. sulphuric acid (75 mL,1407 mmol) dropwise maintaining internal temperature below 20° C. overapproximately 35 minutes. After complete addition, the reaction mixturewas stirred at room temperature over 30 minutes. The reaction was pouredinto a beaker and washed in with ethyl acetate (400 mL) and a littlewater. The mixture was cooled to 15° C. and a solution of sodiumcarbonate (160 g in 1200 mL water) was added over 5 minutes. The mixturewas filtered over a pad of celite and the remaining solids washed withethyl acetate (400 mL). The filtrate phases were separated and theaqueous phase was extracted with ethyl acetate (2×400 mL). The combinedorganics were washed with brine (500 mL), dried over magnesium sulphate,filtered and evaporated to yield a foaming amber oil. This was twicedissolved in acetonitrile (100 mL) and evaporated and the resultingyellow foam dried under vacuum to give the title material (D8) in goodpurity by NMR, consistent spectroscopically with that produced by Method1.

Description 8a

3-Amino-1-methyl-3-[3-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]prop-2-ynyl]pyrrolidin-2-one(D8a)

To a stirred solution of 3-amino-1-methyl-3-prop-2-ynyl-pyrrolidin-2-one(which may be prepared as described in Description 3) (2.3 g, 15.11mmol) in tert-butyl methyl ether (50 mL) was added2-iodo-4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidine (which may beprepared as described in Description 6) (6.05 g, 16.62 mmol).diisopropylamine (6.35 mL, 45.34 mmol) was then added, followed bycopper iodide (57.56 mg, 0.300 mmol) andbis(triphenylphosphine)palladium (II) dichloride (106.07 mg, 0.1500mmol). The reaction was then stirred at room temperature for 5 days. Thereaction mixture was transferred to a separating funnel and the flaskwashed with an additional quantity of tert-butyl methyl ether (15 ml).The organic solution was washed with water (2×50 mL) and brine (50 mL).The organic phase was dried over magnesium sulphate, filtered, and thenthe magnesium sulphate washed with dichloromethane (30 ml). The filtratewas concentrated at reduced pressure to give a yellow foam. The productwas purified by silica gel chromatography eluting with ethyl acetatefollowed by an increasing percentage of a solution of 10% 0.880 ammoniain methanol, to give the title compound (D8a) as a yellow foam (4.71 g).This racemate was consistent by NMR and mass spectroscopy with the Sisomer prepared in Description 8.

Description 9

(5S)-7-Methyl-2-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]non-1-en-6-one(D9)

Method 1: Silver trifluoromethanesulphonate (358.56 mg, 1.4 mmol) wasadded to a solution of(3S)-3-amino-1-methyl-3-[3-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]prop-2-ynyl]pyrrolidin-2-one(2.71 g, 6.98 mmol) (which may be prepared as described in Description8) in MeCN (60 mL) at 50° C. and the reaction was stirred for 3 days.Additional AgOTf (10 mol %) was added and stirring was continued for 24hrs. The solvent was evaporated and the residue was suspended in EtOAc.The organics were washed with water, dried (Na₂SO₄) and the solventevaporated to afford a light brown oil. This was purified using aBiotage Isolera with a 100 g SNAP cartridge, eluting with 0 to 100%(mixture of 1% of 2M NH₃ in MeOH; 9% MeOH; 90% EtOAc) in EtOAc,affording the(5S)-7-methyl-2-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]non-1-en-6-one(D9) (2.51 g, 6.4626 mmol, 92.6% yield) as a light brown solid;

300 MHz NMR δ_(H) (CDCl₃) 1.89-2.00 (1H, m), 2.16-2.25 (1H, m),2.59-2.72 (2H, m), 2.72 (3H, s), 2.92 (3H, s), 3.30-3.45 (2H, m),3.55-3.78 (2H, m), 7.64 (1H, s), 7.79 (2H,d), 8.26 (2H, d).

Method 2: Silver trifluoromethanesulphonate (9.39 g, 36.56 mmol) wasadded in a single batch to a solution of(3S)-3-amino-1-methyl-3-[3-[4-methyl-6-[4-(trifluoromethyl)phenyl]-pyrimidin-2-yl]prop-2-ynyl]pyrrolidin-2-one(which may be prepared as described in Description 8) (71 g, 182.81mmol) in MeCN (1000 mL) and the reaction was heated at 80° C. for 22hours. The solvent was evaporated and the residue dissolved in DCM (1000mL). Saturated NaHCO₃ (500 ml) and water (500 ml) were added and themixture shaken. The phases were separated and the organic layer treatedwith a solution of cysteine (100 g, 825.35 mmol) in water (1500 ml).This mixture was stirred vigorously for 30 minutes. The mixture wasfiltered through a pad of celite, and the celite washed with DCM (2×100ml). The phases were separated and the organic layer placed in a largebeaker. To this was added a solution of cysteine (50 g, 412.68 mmol) inwater (500 ml) and the mixture was stirred for a further 30 minutes. Thephases were separated and the organic layer was washed with a mixture ofsat. brine (500 ml) and water (500 ml). The organic layer was dried(MgSO₄) and the solvent evaporated to afford a dark brown foam. To thefoam was added acetone (50 ml) and almost immediately a thickprecipitate formed. This was swirled for about 5 minutes prior to slowaddition of Et₂O (150 ml) over approx. 10 minutes. After addition, thesuspension was left to stand for 30 minutes. The solid was filtered offand washed with ether (3×30 ml) to afford the title material as a lightbrown solid (D9) (49.24 g), pure by NMR and consistent with thatproduced by Method 1;

Optical Rotation α[D/20]=−141.5 (c=1.12 in CHCl₃).

The mother liquors were evaporated to afford a dark foam. This wasdissolved in acetone (20 ml) and allowed to stand, with a seedingcrystal, for about 15 minutes. Slow crystallization occurred. Themixture was diluted carefully with Et₂O (40 ml) and left in a fridge for18 hours. The supernatant was decanted and the crystalline solid washedwith Et₂O (3×6 ml) to afford an additional crop of (D9) as a lightorange solid (5.31 g) consistent spectroscopically with the earlierbatch.

PREPARATION OF EXAMPLES Example 1(2R,55)-7-Methyl-2-[4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]nonan-6-onehydrochloride (E1)

Concentrated aq. HCl (554.67 μL, 6.46 mmol) was added to a solution ofthe(5S)-8-methyl-3-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]-4,8-diazaspiro[4.4]non-3-en-9-one(2.51 g, 6.46 mmol) (which may be prepared as described in Description9) in DCM (60 mL) at 0° C. Finally, Sodium triacetoxyborohydride (4.11g, 19.39 mmol) was added in a single portion and the resulting mixturewas stirred for 90 mins. The reaction was quenched by the addition ofsat. aq. Na₂CO₃ and stirring was continued for 5 mins. The phases wereseparated, the organic layer was dried (Na₂SO₄) and the solvent wasevaporated to afford an amber oil (2.15 g). This was dissolved in DCE(60 ml) and Boc₂O (2.4 g, 11.01 mmol) was added and the reaction wasstirred at 50° C. for 18 hrs. The solvent was evaporated to afford acrude brown oil. This was purified using a Biotage SP4 with a100 g SNAPcartridge, eluting with EtOAc (8 CV) to elute the faster Syn isomer A,followed by 0 to 10% MeOH/EtOAc to elute the slower anti isomer B. Thesyn isomer A: tert-butyl(2S,5S)-7-methyl-2-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]-6-oxo-1,7-diazaspiro[4.4]-nonane-1-carboxylate(0.6580 g, 1.3414 mmol, 24.4% yield) was obtained as a foam; m/z 491(M+H⁺).

The anti isomer B: tert-butyl(2R,5S)-7-methyl-2-[4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidin-2-yl]-6-oxo-1,7-diazaspiro[4.4]nonane-1-carboxylate(1.9 g, 3.8734 mmol, 70.3% yield), was obtained as a foam;

m/z 491 (M+H⁺),

4M HCl in dioxane (9.68 mL, 38.73 mmol) was added to a solution of theanti isomer B, tert-butyl(2R,5S)-7-methyl-2-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]-6-oxo-1,7-diazaspiro[4.4]nonane-1-carboxylate(1.9 g, 3.87 mmol) in DCM (20 mL) at 20° C. and the reaction stirred for18 hrs. The solvent was evaporated and the residue was suspended inEtOAc. This was treated with sat. NaHCO₃ and the phases separated. Theorganic layer was dried (Na₂SO₄) and the solvent evaporated to afford alight brown oil (1.47 g). This material was dissolved in MeOH andapplied to a SCX (10 g) cartridge. The column was eluted with MeOH,followed by 2M NH₃ in MeOH to afford the(2R,5S)-7-methyl-2-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]nonan-6-one(1.2 g, 3.0738 mmol, 79.4% yield) as a light brown oil;

300 MHz NMR δ_(H) (CDCl₃) 1.86-1.97 (1H, m), 2.10-2.31 (4H, m),2.59-2.68 (1H, m), 2.62 (3H, s), 2.92 (3H, s), 3.10 (1H br.s), 3.27-3.43(2H, m), 4.85 (1H, t), 7.46 (1H, s), 7.77 (2H, d), 8.21 (2H, d).

1M HCl in Et₂O (3.07 mL, 3.07 mmol) was added to a solution of the(2R,5S)-7-methyl-2-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]nonan-6-one(1.2 g, 3.07 mmol) in DCM (20 mL) at 20° C. and the reaction stirred for5 mins. The solvent was evaporated and the residue was trituated fromEt₂O and dried under vacuum at 40° C. to afford the(2R,5S)-7-methyl-2-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]nonan-6-onehydrochloride (El) (1.07 g, 2.7408 mmol, 89.2% yield) as an off whitesolid with 5 mol % ether present;

300 MHz NMR O_(H) (MeOD) 2.26-2.57 (4H, m), 2.61-1.71 (1H, m), 2.69 (3H,s), 2.87-2.98 (1H, s), 2.98 (3H, s), 3.53-3.59 (2H, m), 5.84 (1H, t),7.88 (2H, d), 8.02 (1H, s), 8.95 (2H, d); m/z 391 (M+H⁺); OpticalRotation α[D/22]=+12.1 (c =0.995, MeOH).

Example 2(2R,5S)-7-Methyl-2-[4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]nonan-6-onesulfuric acid salt (E2)

(5S)-7-Methyl-2-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]non-1-en-6-one(which may be prepared as described in Description 9) (78.34 g, 201.7mmol) was added to a 5 L three necked round bottomed flask containing anoverhead stirrer, 500 ml pressure-equalising dropping funnel with anitrogen inlet and thermometer. To this was added DCM (1000 mL) and thestirred mixture cooled to approx. −70° C. The dropping funnel wascharged with a pre-sonicated solution of borane tert-butylamine (19.3 g,221.87 mmol) in DCM (200 mL). The borane complex was added slowlymaintaining the temperature below −70° C. over approx. 30 minutes. Afteraddtion the reaction was stirred at below −70° C. for 90 minutes. Thedropping funnel was charged with 6M HCl (400 ml) and this was addeddropwise over approx. 15 minutes. The reaction temperature warmed to−50° C. during the addition. After addition was complete theacetone/dry-ice bath was removed and the reaction mixture warmed to roomtemperature then stirred for a further 30 minutes. In a separate 10 Lflask was added sodium carbonate (200 g) and water (1 L). To this flaskwas added an overhead stirrer. The reaction mixture was carefully added(note: gas evolution) to the sodium carbonate solution and stirring wasmaintained until gas evolution ceased. The mixture was transfered to a 6L separating funnel and the phases were separated. The aqueous layer waswashed with DCM (2×200 ml) and the combined organics were dried (MgSO₄).The solvent was evaporated to afford7-methyl-2-[4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]nonan-6-oneas an amber oil (77.8 g), a 96:4 ratio of (2R,5S) and (2S,5S) isomers.

A similarly prepared sample was recrystallised from diethyl ether andisohexane to give the free base form of the title material as acolurless solid with a melting point of 66-67° C. Similarly prepared7-methyl-2-[4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]nonan-6-onewith a diastereomeric excess of approximately 92% (49 g, 125.51 mmol) inMeCN (700 mL) was suction filtered through a shallow pad of Hyflo togive a clear yellow solution. To this rapidly stirred solution at 50° C.was added 7.5M sulphuric acid (17.6 mL, 132 mmol) over 5 seconds to givea solution which quickly crystallized. The mixture was left to stand atambient temperature for 2 h then filtered and washed withacetonitrile/Et₂O (1:1) (200 ml) then Et₂O (150 ml) and dried 50° C. togive the title material (E2) in an 82:1 ratio of (2R,5S) and (2S,5S)isomers (50.6 g) assessed by NMR. 300 MHz NMR O_(H) (MeOD) 2.26-2.56(4H, m), 2.64-2.74 (1H, m), 2.69 (3H, s), 2.88-2.98 (1H, m), 2.98 (3H,s), 3.53-3.59 (2H, m), 5.35 (1H, t), 7.78 (2H, d), 8.02 (1H, s), 8.46(2H, d); m/z 391 (M+H⁺).

A similarly prepared sample was recrystallised from acetonitrile to givethe title compound as a cream solid with a melting point of 227-228° C.

Example 3(2R,5S)-7-Methyl-2-[4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]nonan-6-onesulfuric acid salt hydrate (E3)

(2R,5S)-7-Methyl-2-[4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]nonan-6-onesufuric acid salt (which may be formed as described in Example 2) (10mg) was recrystalised by slow cooling in a dewer flask from hot acetone(2 ml), with sufficient added water to cause solubilisation, to form thetitle compound (E3), the crystalline monohydrate. This was shown to havethe (2R,5S)-configuration by single crystal X-ray crystallography.

BIOLOGICAL ASSAYS

The compounds of the invention were tested in a QPatch NaV1.7 assay.

QPatch NaV1.7 Assay

HEK293-hNaV1.7 cells were grown in DMEM-F12+10% FBS culture media at 37°C. At a confluency of 50-70% cells were dissociated from culture flasks& triturated to ensure unicellular cell suspension; cell density wasmeasured & adjusted to 2-3×10⁶ cells/ml. Recordings were obtained usingQPatch16×. The external solution was (in mM): NaCl, 128; KCl, 5; MgCl₂,2; CaCl₂, 2; Glucose, 30; HEPES, 15; pH 7.3, 305-315 mOsm. Followingseal formation and whole-cell access using internal solution (containingin mM: CsF, 135; EGTA/CsOH, 1/5; HEPES 10; NaCl, 10; pH 7.3, 310-320mOsM), voltage pulse protocols were applied. Initially a steady stateinactivation voltage protocol was used to determine the half-maximalvoltage for steady state inactivation (V1/2 SSI). Two holding voltageswere used to determine test drug inhibition: −90 mV, where most of thechannels are in a closed state; and V1/2 SSI, where half of the channelsare inactivated. Currents were elicited every 10 seconds by stepping toa membrane potential of 0 mV for 20 ms. Four-point cumulativeconcentration responses were derived by determining the peak currentamplitude at each concentration of test drug over 120 secondapplication. Curves were fitted with the Hill equation yielding pIC50values at −90 mV and V1/2 SSI holding potentials.

Example QP Nav1.7 −90 QP Nav1.7 SSI Number mV pIC50 vhalf pIC50 1 3.95.7

What is claimed is: 1-10. (canceled)
 11. A method for treating a diseaseor condition mediated by modulation of voltage-gated sodium channels,comprising: administering to the patient an effective amount of acompound of formula (I) which is7-methyl-2-[4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]nonan-6-one:

or a pharmaceutically acceptable salt or solvate thereof.
 12. The methodof claim 11, wherein the compound of formula (I) is a compound offormula (Ia):

or a pharmaceutically acceptable salt or solvate thereof.
 13. The methodof claim 11, wherein the compound of formula (I) or a pharmaceuticallyacceptable salt or solvate thereof is(2R,5S)-7-Methyl-2-[4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]nonan-6-onehydrochloride (E1).
 14. The method of claim 11, wherein the compound offormula (I) or a pharmaceutically acceptable salt or solvate thereof is(2R,5S)-7-Methyl-2-[4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]nonan-6-onesulfuric acid salt (E2).
 15. The method of claim 11, wherein thecompound of formula (I) or a pharmaceutically acceptable salt or solvatethereof is(2R,5S)-7-Methyl-2-[4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]nonan-6-onesulfuric acid salt hydrate (E3).
 16. The method of claim 12, wherein thecompound of formula (Ia) or a pharmaceutically acceptable salt orsolvate thereof is(2R,5S)-7-Methyl-2-[4-methyl-6-[4-(triflouromethyl)-phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]nonan-6-onehydrochloride (E1).
 17. The method of claim 12, wherein the compound offormula (Ia) or a pharmaceutically acceptable salt or solvate thereof is(2R,5S)-7-Methyl-2-[4-methyl-6-[4-(triflouromethyl)-phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]nonan-6-onesulfuric acid salt (E2).
 18. The method of claim 12, wherein thecompound of formula (Ia) or a pharmaceutically acceptable salt orsolvate thereof is(2R,5S)-7-Methyl-2-[4-methyl-6-[4(triflouromethyl)-phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]nonan-6-onesulfuric acid salt hydrate (E3).
 19. A method for treating a disease orcondition mediated by modulation of voltage-gated sodium channels,comprising administering to a patient a pharmaceutical compositioncomprising a compound of formula (I) as defined in claim 11, wherein thecompound or a pharmaceutically acceptable salt or solvate thereof isselected from the group consisting of:7-methyl-2-[4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]nonan-6-oneor a pharmaceutically acceptable salt or solvate thereof:(2R,5S)-7-Methyl-2-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]nonan-6-onehydrochloride (E1);(2R,5S)-7-Methyl-2-[4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]nonan-6-onesulfuric acid salt (E2); and(2R,5S)-7-Methyl-2-[4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]nonan-6-onesulfuric acid salt hydrate (E3), and wherein the composition furtherincludes at least one of a pharmaceutically acceptable carrier, diluentand excipient.
 20. The method of claim 19, wherein the compound is thecompound having the structural formula (Ia) or a pharmaceuticallyacceptable salt or solvate thereof.
 21. The method of claim 20, whereinthe compound or a pharmaceutically acceptable salt or solvate thereof is(2R,5S)-7-Methyl-2-[4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]nonan-6-onehydrochloride (E1).
 22. The method of claim 20, wherein the compound ora pharmaceutically acceptable salt or solvate thereof is(2R,5S)-7-Methyl-2-[4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]nonan-6-onesulfuric acid salt (E2).
 23. The method of claim 20, wherein thecompound or a pharmaceutically acceptable salt or solvate thereof is(2R,5S)-7-Methyl-2-[4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]nonan-6-onesulfuric acid salt hydrate (E3).